Zinc Finger Protein
Zinc finger proteins are a diverse class of proteins characterized by their distinctive structural motifs, which involve one or more zinc ions coordinating with cysteine and/or histidine residues to stabilize specific protein folds. This intricate structure allows these proteins to bind to DNA, RNA, or other proteins with high specificity. They are fundamental to many biological processes, acting as critical regulators of gene expression, DNA repair, replication, and various signaling pathways. Their ability to recognize and interact with specific nucleic acid sequences or protein partners makes them essential components of cellular machinery across all domains of life.
Clinical Relevance
The widespread involvement of zinc finger proteins in cellular regulation makes them significant players in human health and disease. For instance, the gene BCL11A, located on chromosome 2p15, encodes a zinc finger protein that has been identified as a quantitative trait locus (QTL) influencing F cell production. [1] F cells measure the presence of fetal hemoglobin, a heritable trait in adults that can substantially impact the phenotypic diversity and severity of conditions such as sickle cell disease and beta thalassemia. [1] Variants within BCL11A that affect F cell production can therefore modulate disease outcomes, highlighting the clinical importance of this zinc finger protein in hematological disorders.
Social Importance
Understanding zinc finger proteins holds considerable social importance due to their broad implications for disease research and therapeutic development. Their role in regulating gene expression makes them attractive targets for medical interventions. Advances in biotechnology have led to the development of zinc finger nucleases (ZFNs), which are engineered proteins that can precisely target and modify specific DNA sequences. These tools have revolutionized gene editing, offering potential avenues for correcting genetic mutations responsible for various diseases. Furthermore, the identification of zinc finger proteins like BCL11A as genetic modifiers of disease traits contributes to a deeper understanding of complex human diseases, paving the way for improved diagnostics, personalized prognoses, and the development of novel therapies.
Methodological and Statistical Constraints
Genetic association studies, particularly those employing genome-wide association study (GWAS) designs, often face inherent methodological and statistical limitations that can impact the interpretation and generalizability of their findings. A primary concern is the composition and size of study cohorts. Many studies rely on specific populations, such as adolescent twins and their siblings, or adult female monozygotic twins, which may not accurately represent the broader general population. [2] Furthermore, participation in volunteer-based studies can introduce selection or participation bias, potentially skewing the sample away from a truly random population representation. [2] The moderate size of some cohorts also leads to inadequate statistical power, increasing the risk of false negative findings and limiting the ability to detect genetic variants with smaller effect sizes. [3] This lack of power can also hinder the comprehensive study of candidate genes or the identification of novel variants, as current GWAS often utilize only a subset of all available SNPs, potentially missing crucial genetic information. [4]
Additionally, the statistical assumptions underlying effect size estimations and explained genetic variance can introduce uncertainties. The calculation of estimated effect sizes and the proportion of variance explained by SNPs often relies on assumptions about the accuracy of phenotypic variance and heritability estimates, which may not always hold true. [2] While family-based association tests are robust to population stratification, their power can be limited compared to total association tests, as they only utilize information from individuals with heterozygous parents. [2] The ultimate validation of genetic associations requires independent replication in diverse cohorts, a process that is frequently challenging. Studies often report that only a fraction of previously identified associations are successfully replicated, which can be attributed to false positive findings in initial studies, key differences between cohorts, or insufficient statistical power in replication attempts. [3] Even when associations are found within the same gene region, non-replication at the SNP level can occur if different studies identify SNPs that are in strong linkage disequilibrium with a causal variant but not with each other, suggesting the complexity of causal architecture. [5]
Generalizability and Phenotypic Measurement Issues
The generalizability of findings from genetic association studies is significantly constrained by the demographic characteristics of the study populations. Many cohorts are predominantly composed of individuals of white European ancestry, often middle-aged to elderly, which limits the applicability of the results to younger individuals or populations of different ethnic or racial backgrounds. [3] This lack of diversity means that genetic effects observed may not be consistent across all populations, potentially overlooking important ancestry-specific genetic influences. Moreover, the definition and measurement of phenotypes can introduce variability and confounders. For instance, serum markers for iron status are known to be influenced by environmental factors such as the time of day blood samples are collected and menopausal status. [2] If these factors are not consistently controlled or adequately adjusted for across different study participants or cohorts, they can confound the observed associations between genetic variants and phenotypes. [2]
Furthermore, the statistical treatment of phenotypic data can present challenges. Many biological traits may not follow a normal distribution, necessitating complex statistical transformations (e.g., log, Box-Cox, or probit transformations) to approximate normality for analysis. [6] The choice and appropriateness of these transformations can influence the results and their interpretation. In some cases, incomplete phenotypic data for a small percentage of individuals within a cohort can also introduce analytical complexities or reduce the effective sample size for certain traits. [6] These issues underscore the importance of meticulous phenotyping protocols and robust statistical approaches to ensure the reliability and broader applicability of genetic association findings.
Unexplained Genetic Variance and Causal Complexity
Despite the success of GWAS in identifying numerous genetic associations, significant knowledge gaps remain regarding the complete genetic architecture of complex traits. The proportion of phenotypic variance explained by identified SNPs is often based on assumptions about overall phenotypic variance and heritability, and a substantial portion of heritability, known as "missing heritability," frequently remains unexplained by common variants. [2] This suggests that many genetic influences, including rare variants, structural variations, or complex gene-gene and gene-environment interactions, are not fully captured by current GWAS designs. For example, environmental factors such as blood collection time and menopausal status are known to influence various serum markers, and while some studies attempt to adjust for these, the full spectrum of gene-environment interactions and their impact on phenotypes is often not comprehensively explored. [2]
Moreover, the identification of an associated SNP does not always pinpoint the causal variant itself. Different SNPs within the same gene or region might show association across studies, indicating either multiple causal variants or that the identified SNPs are merely markers in linkage disequilibrium with an unknown causal variant. [5] The absence of sex-specific analyses in some studies also represents a limitation, as certain genetic associations may manifest differently or exclusively in males or females, leading to undetected sex-specific effects. [4] Ultimately, genetic association studies provide valuable insights into genetic predispositions, but the findings require further functional validation to elucidate the precise biological mechanisms through which these variants exert their effects. Without this deeper functional understanding, the full clinical or biological significance of many identified associations remains an open question. [3]
Variants
The human genome harbors a vast array of genes encoding zinc finger proteins (ZFPs), which are critical for diverse cellular functions, primarily acting as DNA- or RNA-binding proteins that regulate gene expression, protein-protein interactions, and enzymatic activities. One such gene, located on chromosome 2p15, encodes a zinc-finger protein that influences F cell production. [1] F cells are red blood cells containing fetal hemoglobin (HbF), which is instrumental in mitigating the clinical severity of conditions like beta-thalassemia and sickle cell disease. Another prominent zinc finger protein, BCL11A, functions as a C2H2-type zinc finger transcription factor and is a key repressor of HbF synthesis in adults. [7] Specific genetic variations within or near the BCL11A gene, such as rs11886868 and rs10837540, are strongly associated with higher persistent levels of HbF, offering a genetic explanation for improved outcomes in individuals with beta-thalassemia. These variants likely modulate BCL11A’s expression or its ability to silence HbF production.
Beyond direct gene regulation by zinc finger proteins, zinc itself is fundamental for numerous biological processes, including enzyme function and protein stability, with specific transporters maintaining cellular zinc balance. The SLC30A8 gene, which encodes the zinc transporter 8 (ZnT-8), is a beta-cell-specific protein found in insulin secretory granules and is crucial for the proper storage and release of insulin. [8] Genetic variants in SLC30A8 are linked to an increased susceptibility to type 2 diabetes, underscoring the vital connection between zinc metabolism and glucose homeostasis. Similarly, the MLXIPL gene, encoding a basic helix-loop-helix leucine zipper transcription factor, plays a role in regulating lipid metabolism, with its genetic variations associated with plasma triglyceride levels. [9] While not a zinc finger protein, its DNA-binding and transcriptional control mechanisms are functionally analogous, illustrating how various transcription factors, often influenced by or interacting with zinc, coordinate complex metabolic pathways. Furthermore, variants in the glucokinase regulator gene, GCKR, including rs780094, are associated with dyslipidemia, reflecting broader genetic determinants of metabolic health. [10]
Genetic variations also extend to genes involved in inflammatory responses and other critical metabolic pathways, which can indirectly interact with or be influenced by zinc-dependent processes. For example, the HNF1A gene encodes hepatocyte nuclear factor-1 alpha, a transcription factor vital for the function of liver and pancreatic beta-cells. Polymorphisms within HNF1A, including a cluster of five single nucleotide polymorphisms—rs7310409, rs2393775, rs7979473, rs2393791, and rs7979478—found in perfect linkage disequilibrium within its first intron, are associated with circulating C-reactive protein (CRP) levels, a key marker of inflammation. [11] Additionally, the HK1 gene, which codes for hexokinase 1, has novel associations with glycated hemoglobin levels in individuals without diabetes, indicating broader genetic influences on glucose metabolism. [8] Variants in FADS1 (fatty acid desaturase 1) also affect the efficiency of fatty acid desaturation, leading to alterations in glycerophospholipid metabolism and the levels of various phosphatidylcholines and phosphatidylethanolamines. [12]
Iron metabolism, a process intricately linked with zinc homeostasis, is significantly shaped by genetic variants in genes such as TF (transferrin) and HFE (hemochromatosis). Transferrin, the primary iron-binding protein in blood plasma, can have its serum levels affected by variations in the TF gene. [2] The C282Y mutation in the HFE gene, a well-known cause of hereditary hemochromatosis, profoundly impacts iron absorption and storage, demonstrating how genetic factors regulate systemic iron balance. Furthermore, hemostatic factors and platelet function are modulated by specific genetic variations; for instance, the cis-acting SNP rs561241 near the F7 gene is associated with factor VII levels. [4] The PDGFC gene (platelet derived growth factor-C), which is involved in platelet biology and highly expressed in vascular smooth muscle cells, also contains variants like rs6811964 that contribute to these complex hemostatic phenotypes. [4]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| chr11:116784884 | N/A | triglyceride measurement zinc finger protein measurement level of parathyroid hormone in blood serum level of clusterin-like protein 1 in blood serum |
Definition and General Characteristics
A zinc finger protein refers to a broad class of proteins, each encoded by specific genes within the human genome. These proteins are characterized by the presence of one or more zinc finger motifs, which are structural domains typically stabilized by the coordination of zinc ions. The precise definition from a genetic perspective involves the identification of a gene that codes for such a protein.. [1] These motifs often enable the proteins to interact with DNA, RNA, or other proteins, playing diverse roles in cellular regulation and function.
Genetic Location and Functional Significance
A gene encoding a zinc finger protein has been identified and mapped to chromosome 2p15. [1] This specific gene is notable for influencing F cell production, indicating a significant role in cellular processes related to F cells. [1] The identification of a quantitative trait locus (QTL) for F cell production linked to such a gene underscores its functional importance in genetic variation of this trait. This highlights how genetic variants within or near genes encoding zinc finger proteins can contribute to observable phenotypic differences.
Related Terminology and Distinctions
While sharing the common element of zinc, zinc finger proteins are distinct from other zinc-related proteins such as zinc transporters. For instance, the zinc transporter ZnT-8 represents a different class of protein, characterized by its specific role in transporting zinc ions rather than directly influencing gene expression or cell production. [13] ZnT-8 is specifically expressed in beta-cells, localized within insulin secretory granules, and plays a crucial role in glucose-induced insulin secretion . [13], [14] This distinction highlights the diverse biological functions of proteins associated with zinc, ranging from transcriptional regulation to ion transport.
BCL11A and Its Role as a Zinc Finger Protein
Zinc finger proteins are a diverse class of proteins characterized by structural motifs that coordinate zinc ions, enabling them to bind to DNA, RNA, proteins, or lipids. These interactions are crucial for a wide array of biological functions, particularly in gene regulation. BCL11A (B-cell CLL/lymphoma 11A) is a prominent example of a zinc finger protein, specifically identified as a transcription factor. [15] Its genetic locus has been mapped to chromosome 2p15. [1] The protein's structure, with its zinc finger domains, allows it to recognize and bind to specific DNA sequences, thereby modulating the expression of target genes.
As a critical biomolecule, BCL11A plays a significant role in various cellular processes by acting as a transcriptional regulator. Its ability to influence gene expression positions it at the nexus of regulatory networks that dictate cell fate and function. The specific binding capabilities conferred by its zinc finger motifs enable BCL11A to either activate or repress gene transcription, depending on the context and its interacting partners. This regulatory capacity underlies its involvement in complex biological pathways, including those related to cellular development and differentiation.
Genetic Regulation of Fetal Hemoglobin Production
The production of F cells, which contain fetal hemoglobin, is a heritable quantitative trait in adults that exhibits substantial phenotypic diversity and has significant implications for certain blood disorders. [1] A quantitative trait locus (QTL) influencing F cell production has been precisely mapped to the BCL11A gene on chromosome 2p15. [1] This genetic region, associated with BCL11A, is responsible for a notable 15.1% of the observed variance in F cell production, highlighting its major contribution to this complex trait. [1]
The genetic mechanisms underlying fetal hemoglobin regulation involve intricate gene expression patterns influenced by specific regulatory elements. Variations within the BCL11A gene or its regulatory regions can alter its function, consequently impacting the levels of fetal hemoglobin. Modulating fetal hemoglobin levels is particularly relevant in conditions like sickle cell disease and beta thalassemia, where higher levels of fetal hemoglobin can ameliorate the severity of the disease phenotype. [7] This genetic control over fetal hemoglobin represents a crucial pathway for understanding and potentially treating these hematological disorders.
Molecular Mechanisms of BCL11A Action
BCL11A functions as a transcription factor, orchestrating cellular processes through its direct influence on gene expression. [15] Its molecular activity involves forming complexes with other critical proteins, such as its interaction with BCL6 in the nuclear paraspeckles of germinal center B cells. [15] These protein-protein interactions are integral to BCL11A's ability to integrate into broader regulatory networks and exert its specific transcriptional effects.
A key molecular mechanism by which BCL11A regulates gene expression is through the recruitment of enzymes like SIRT1 to promoter regions. [16] This recruitment leads to histone deacetylation, a crucial epigenetic modification that results in transcriptional repression of target genes. [16] By controlling the accessibility of DNA to the transcriptional machinery, BCL11A effectively silences genes involved in specific cellular functions, thereby guiding developmental pathways and maintaining cellular homeostasis.
Pathophysiological Impact and Tissue-Level Effects
The physiological importance of BCL11A extends to its essential role in normal lymphoid development. [17] Disruptions in BCL11A's function can lead to significant developmental processes being perturbed, impacting the immune system's proper formation and function. This highlights its critical involvement in maintaining healthy cellular differentiation and tissue integrity within the hematopoietic system.
Beyond its developmental roles, BCL11A has significant pathophysiological implications, notably its involvement in lymphoid malignancies. [18] Aberrant expression or function of BCL11A can contribute to the initiation and progression of certain cancers, underscoring its role in disease mechanisms. Furthermore, the _BCL11A_XL splice variant, a specific form of the BCL11A transcription factor, exhibits distinct distribution patterns in both normal and malignant tissues and serves as a marker for plasmacytoid dendritic cells. [19] Its systemic consequences are evident in its impact on F cell production, which, when modulated, can compensate for homeostatic disruptions in red blood cell function, particularly in individuals with sickle cell disease and beta thalassemia.
Transcriptional Regulation and Cellular Signaling
Zinc finger proteins are fundamentally involved in the intricate pathways of transcriptional regulation, acting primarily as DNA-binding proteins that modulate gene expression in response to various cellular cues. These proteins often serve as critical nodes in intracellular signaling cascades, where receptor activation by external stimuli can trigger a series of phosphorylation events or other modifications that alter the activity or localization of specific zinc finger proteins. Once activated, these proteins bind to specific DNA sequences within gene promoters or enhancers, thereby initiating or repressing the transcription of target genes. This regulatory mechanism forms the basis of cellular responses to environmental changes and developmental programs, with sophisticated feedback loops ensuring precise control over gene expression. For example, a specific zinc finger protein located on chromosome 2p15 has been identified as influencing F cell production, demonstrating its direct role in regulating cellular differentiation or maintenance pathways. [1]
Metabolic Homeostasis and Gene Regulation
Through their role in gene regulation, zinc finger proteins exert significant influence over various metabolic pathways, including energy metabolism, biosynthesis, and catabolism. By controlling the expression of genes encoding metabolic enzymes, transporters, or regulatory factors, these proteins contribute to maintaining metabolic homeostasis and controlling metabolic flux. A compelling example involves the zinc transporter SLC30A8 (ZnT-8), which is critical for glucose-induced insulin secretion and is associated with type 2 diabetes. [13] While zinc finger proteins depend on zinc for their structural integrity and function, they can also transcriptionally modulate the expression of such transporters, thereby influencing cellular zinc levels and, consequently, processes like insulin secretion and the proper activity of other zinc-dependent metabolic regulators. This highlights how zinc finger proteins are integral to metabolic regulation, extending to the control of essential mineral transporters and their impact on complex metabolic traits such as uric acid levels, influenced by genes like SLC2A9 (GLUT9). [20]
Post-Translational Control and Allosteric Modulation
The activity and functional specificity of zinc finger proteins are extensively fine-tuned by various regulatory mechanisms, including post-translational modifications and allosteric control. Protein modifications such as phosphorylation, acetylation, or ubiquitination can alter a zinc finger protein's DNA-binding affinity, its ability to interact with co-regulators, its subcellular localization, or its stability. For instance, the ubiquitin ligase PJA1, which contains a RING-H2 zinc finger domain, exemplifies how these proteins can directly participate in post-translational regulation by targeting other proteins for ubiquitination and subsequent degradation. [21] Furthermore, allosteric control mechanisms, where the binding of small molecules, ions, or other proteins to a distinct site on a zinc finger protein induces conformational changes, can modulate its activity without directly affecting its DNA-binding domain. These intricate regulatory layers ensure that zinc finger proteins respond dynamically to intracellular signals and maintain precise control over their downstream targets.
Systems-Level Integration and Pathway Crosstalk
Zinc finger proteins are key components in the systems-level integration of biological information, facilitating pathway crosstalk and contributing to complex network interactions. Their ability to bind specific DNA sequences allows them to respond to convergent signals from multiple pathways, integrating diverse stimuli into a coherent transcriptional output. This enables a single zinc finger protein to serve as a hub, influencing genes across various biological processes and ensuring coordinated cellular responses. The hierarchical regulation often observed in biological systems frequently places zinc finger proteins at critical junctures, where they act as master regulators that control entire gene networks. The emergent properties of these complex networks, such as cellular differentiation or adaptation, are often a direct consequence of the integrated regulatory activities orchestrated by families of zinc finger proteins.
Disease Pathogenesis and Therapeutic Avenues
Dysregulation of zinc finger protein function or expression is frequently implicated in the pathogenesis of various diseases, ranging from developmental disorders to metabolic diseases and cancer. Alterations in these proteins can lead to aberrant gene expression, disrupting critical pathways and contributing to disease phenotypes. For instance, the involvement of a zinc finger protein in F cell production suggests its potential role in conditions affecting erythropoiesis or hemoglobin synthesis. [1] Similarly, dysregulation of zinc finger proteins that modulate genes like SLC30A8 or SLC2A9, which are associated with type 2 diabetes and uric acid levels, respectively, can contribute to metabolic disorders. Understanding these pathway dysregulations can reveal compensatory mechanisms the body attempts to employ and identify specific zinc finger proteins or their associated pathways as promising therapeutic targets. Modulating the activity, expression, or stability of disease-relevant zinc finger proteins offers potential strategies for novel therapeutic interventions.
Genetic Modulation of Fetal Hemoglobin Production
Research indicates that a Quantitative Trait Locus (QTL) located on chromosome 2p15, which encompasses a gene encoding a zinc-finger protein, significantly influences F cell production. [1] This genetic association highlights the role of variations within this zinc-finger protein gene in modulating the levels of fetal hemoglobin (HbF)-containing red blood cells. The ability of a specific genetic locus to impact F cell production offers crucial insights into the genetic architecture underlying individual differences in hematological traits and responses, which can be foundational for understanding disease susceptibility and progression.
Relevance in Hemoglobinopathies
The identified role of a zinc-finger protein in modulating F cell production holds substantial clinical relevance for individuals affected by hemoglobinopathies, such as sickle cell disease and beta-thalassemia. In these conditions, elevated levels of fetal hemoglobin are known to mitigate disease severity by partially compensating for the dysfunctional adult hemoglobin. [1] Consequently, genetic variants within this zinc-finger protein gene that are associated with higher F cell levels could serve as intrinsic protective factors, potentially predicting a milder clinical course or a more favorable response to therapeutic interventions aimed at inducing HbF. This understanding facilitates more personalized approaches to patient management and risk assessment in these complex genetic disorders.
Diagnostic and Prognostic Utility
Genetic polymorphisms within the zinc-finger protein gene located on chromosome 2p15 may offer valuable diagnostic and prognostic insights in clinical settings. Identifying specific variants that influence F cell production could enable more precise risk stratification for individuals diagnosed with or predisposed to hemoglobinopathies. [1] For instance, patients carrying alleles associated with higher F cell levels might be identified as having a more benign prognosis or being more receptive to specific treatments, thereby guiding clinicians in tailoring therapeutic strategies. Integrating such genetic markers into routine diagnostic and monitoring protocols could advance personalized medicine, optimizing patient care and potentially improving long-term outcomes.
References
[1] Menzel, S et al. "A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15." Nat Genet, vol. 39, no. 10, 2007, pp. 1197-9.
[2] Benyamin, B et al. "Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels." Am J Hum Genet, vol. 83, no. 6, 2008, pp. 693-703.
[3] Benjamin, E. J., et al. "Genome-wide association with select biomarker traits in the Framingham Heart Study." BMC Med Genet, vol. 8, suppl. 1, 28 Sept. 2007, p. S11.
[4] Yang, Q et al. "Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study." BMC Med Genet, vol. 8, suppl. 1, 2007, S12.
[5] Sabatti, C., et al. "Genome-wide association analysis of metabolic traits in a birth cohort from a founder population." Nat Genet, vol. 40, no. 12, Dec. 2008, pp. 1394–1402.
[6] Melzer, D., et al. "A genome-wide association study identifies protein quantitative trait loci (pQTLs)." PLoS Genet, vol. 4, no. 5, 9 May 2008, p. e1000072.
[7] Uda, M et al. "Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia." Proc Natl Acad Sci U S A, vol. 105, no. 5, 2008, pp. 1621-6.
[8] Pare, G et al. "Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the Women's Genome Health Study." PLoS Genet, vol. 4, no. 12, 2008, e1000322.
[9] Kooner, JS et al. "Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides." Nat Genet, vol. 40, no. 2, 2008, pp. 149-51.
[10] Wallace, C et al. "Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia." Am J Hum Genet, vol. 82, no. 1, 2008, pp. 139-49.
[11] Reiner, AP et al. "Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein." Am J Hum Genet, vol. 82, no. 5, 2008, pp. 1193-201.
[12] Gieger, C et al. "Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum." PLoS Genet, vol. 4, no. 11, 2008, e1000282.
[13] Chimienti, F., Devergnas, S., Favier, A., & Seve, M. (2004). Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes, 53(9), 2330–2337.
[14] Chimienti, F., Devergnas, S., Pattou, F., Schuit, F., Garcia-Cuenca, R., et al. (2006). In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. Journal of Cell Science, 119(20), 4199–4206.
[15] Liu, H., et al. "Functional studies of BCL11A: characterization of the conserved BCL11A-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells." Mol Cancer, vol. 5, 2006, p. 18.
[16] Senawong, T., Peterson V-J, Leid M. "BCL11A-dependent recruitment of SIRT1 to a promoter template in mammalian cells results in histone deacetylation and transcriptional repression." Arch Biochem Biophys, vol. 434, 2005, pp. 316-325.
[17] Liu, P., et al. "Bcl11a is essential for normal lymphoid development." Nat Immunol, vol. 4, 2003, pp. 525-532.
[18] Satterwhite, E., et al. "The BCL11 gene family: involvement of BCL11A in lymphoid malignancies." Blood, vol. 98, 2001, pp. 3413-3420.
[19] Pulford, K., et al. "The BCL11AXL transcription factor: its distribution in normal and malignant tissues and use as a marker for plasmacytoid dendritic cells." Blood, vol. 108, 2006, pp. 3413-3420.
[20] Li, S., et al. (2007). The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genetics, 3(11), e194.
[21] Yu, P., Chen, Y., Tagle, D. A., & Cai, T. (2002). PJA1, encoding a RING-H2 finger ubiquitin ligase, is a novel human X chromosome gene abundantly expressed in brain. Genomics, 79(6), 869–874.