Affinage

BCL11A

BCL11 transcription factor A · UniProt Q9H165

Length
835 aa
Mass
91.2 kDa
Annotated
2026-06-09
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BCL11A is a sequence-specific zinc-finger transcriptional repressor that governs developmental gene-expression switches across erythroid, immune, and neural lineages (PMID:19056937, PMID:12196208). In erythroid cells it is the principal developmental silencer of fetal hemoglobin: full-length isoforms are restricted to adult erythroid cells and directly occupy the beta-globin cluster, and its loss re-activates gamma-globin (HBG1/2) (PMID:19056937, PMID:19657335). Repression is achieved through a dedicated zinc-finger cluster (ZF4-6) that recognizes a TGACCA motif at the duplicated ~-115 bp site in the gamma-globin promoters, and naturally occurring HPFH mutations that disrupt this motif abrogate BCL11A binding and de-repress HbF (PMID:29606353, PMID:29610478). BCL11A nucleates a corepressor machinery containing the LSD1/CoREST demethylase complex, DNMT1, and SIRT1, and reorganizes the locus through long-range chromosomal loops and cooperation with SOX6 (PMID:20395365, PMID:23576758, PMID:15639232); acute degradation shows that transcriptional re-activation precedes chromatin opening and is uncoupled from promoter DNA methylation (PMID:35839780). Tetramerization via the N-terminal ZnF0 stabilizes the protein and is required for corepressor engagement and gamma-globin silencing (PMID:39607926). Its erythroid expression is set by an intronic GATA1-bound enhancer activated by KLF1 and ATF4 (downstream of HRI) and repressed developmentally by HIC2, itself controlled by let-7 microRNAs, while LIN28B suppresses BCL11A translation (PMID:20676097, PMID:24115442, PMID:32299090, PMID:35941187, PMID:38364109, PMID:31959994). Beyond erythropoiesis, BCL11A is required cell-intrinsically for B-lymphopoiesis upstream of EBF1/PAX5 and for plasmacytoid dendritic cell commitment via E2-2, and it restrains apoptosis by regulating Bcl2/Mdm2 and antagonizing p53 (PMID:12717432, PMID:24591644, PMID:23230003). In the developing nervous system it directly represses Sema3c to control cortical neuron migration, represses Tbr1 to specify projection-neuron subtype identity, and activates Bcl6 to ensure cortical neuron survival (PMID:26182416, PMID:25972180, PMID:35766181). BCL11A haploinsufficiency causes a neurodevelopmental disorder with intellectual disability, abnormal behavior, and microcephaly, modeled by loss-of-function variants and Bcl11a-haploinsufficient mice (PMID:27453576).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    Established BCL11A as an autonomous sequence-specific DNA-binding transcriptional repressor, defining its core molecular activity independent of COUP-TF partners.

    Evidence SELEX binding selection and reporter repression assays in transfected cells

    PMID:12196208

    Open questions at the time
    • GC-rich GGCCGG motif differs from the later-defined erythroid TGACCA motif
    • no physiological target gene identified at this stage
  2. 2003 High

    Defined BCL11A's cell-intrinsic requirement for B-lymphopoiesis, placing it upstream of the EBF1/PAX5 transcriptional program.

    Evidence Bcl11a knockout mice and fetal-liver transplantation with EBF1/PAX5 expression analysis

    PMID:12717432

    Open questions at the time
    • direct vs indirect regulation of Ebf1/Pax5 not resolved
    • molecular mechanism of lymphoid commitment not defined
  3. 2008 High

    Identified BCL11A as the developmental-stage-specific repressor of fetal hemoglobin, opening the dominant therapeutic axis for hemoglobinopathies.

    Evidence ChIP occupancy at the beta-globin locus and shRNA knockdown in primary adult erythroid cells

    PMID:19056937

    Open questions at the time
    • direct vs looping-mediated repression not distinguished
    • corepressor partners unknown
  4. 2009 High

    Demonstrated that BCL11A is required in vivo for gamma-globin silencing, validating the genetic switch in a humanized model.

    Evidence Bcl11a-null mice carrying the human beta-globin locus

    PMID:19657335

    Open questions at the time
    • mechanism of silencing in vivo not addressed
    • upstream regulators unknown
  5. 2010 High

    Resolved the regulatory architecture: BCL11A silences gamma-globin through long-range chromosomal looping and cooperation with SOX6, and is itself activated by KLF1.

    Evidence ChIP-chip, 3C, Co-IP with SOX6, and KLF1 knockdown in adult erythroid progenitors

    PMID:20395365 PMID:20676097

    Open questions at the time
    • corepressor enzymatic activities not yet identified
    • direct promoter contact vs looping contribution not separated
  6. 2013 High

    Identified the corepressor machinery (LSD1/CoREST, DNMT1) and the erythroid-specific intronic GATA1 enhancer that drives lineage-restricted BCL11A expression, defining the therapeutic target window.

    Evidence Proteomic interaction screen with in vivo corepressor knockouts; GWAS fine-mapping and genome-engineering enhancer deletion

    PMID:23576758 PMID:24115442 PMID:24371119

    Open questions at the time
    • stoichiometry and order of corepressor assembly unresolved
    • whether DNMT1 acts via de novo methylation at HBG not established here
  7. 2015 High

    Saturating mutagenesis pinpointed minimal critical enhancer sequences, converting BCL11A into a precision genome-editing target for HbF re-induction.

    Evidence Pooled CRISPR-Cas9 saturating mutagenesis, primary progenitor editing, and mouse transgenesis

    PMID:26375006

    Open questions at the time
    • primate-specificity of critical sequences limits model translation
    • trans-acting factors at the GATA1 site only partially mapped
  8. 2016 High

    Distinguished BCL11A from a parallel HbF repressor (LRF/ZBTB7A acting via NuRD), establishing that two independent corepressor pathways silence gamma-globin.

    Evidence ChIP, knockdown, and epistasis between LRF and BCL11A pathways

    PMID:26816381

    Open questions at the time
    • whether the two pathways converge at chromatin not resolved
    • BCL11A-NuRD relationship not addressed
  9. 2018 High

    Defined the direct DNA-recognition mechanism: BCL11A uses ZF4-6 to bind a TGACCA motif at the ~-115 bp gamma-globin site, with HPFH mutations confirming functional binding in patients.

    Evidence Protein binding microarray, CUT&RUN, CRISPR editing of promoter motifs, and HPFH mutation analysis

    PMID:29606353 PMID:29610478

    Open questions at the time
    • structural basis of ZF4-6/DNA contact not solved here
    • relationship of direct binding to looping not integrated
  10. 2020 High

    Established multi-layered upstream control of BCL11A dosage through translational suppression by LIN28B and transcriptional activation by the HRI-ATF4 stress axis.

    Evidence Ribosome profiling and LIN28B-mRNA interaction studies; CRISPR screen with ATF4 ChIP and HRI-deficient mice

    PMID:31959994 PMID:32299090

    Open questions at the time
    • physiological trigger of HRI-ATF4 control of BCL11A unclear
    • interplay between translational and transcriptional control not quantified
  11. 2022 High

    Defined developmental repression of BCL11A by HIC2 via steric exclusion of GATA1 at the enhancer, and showed acute BCL11A loss reactivates HBG transcription before chromatin/methylation changes.

    Evidence ChIP, ATAC-seq, 3C and crystallography of HIC2/GATA1; dTAG PROTAC acute degradation with multi-omics

    PMID:35839780 PMID:35941187

    Open questions at the time
    • temporal step linking BCL11A loss to corepressor release not visualized
    • whether methylation changes follow as a consequence not established
  12. 2024 High

    Established that ZnF0-mediated tetramerization stabilizes BCL11A protein and is mechanically required for corepressor engagement and gamma-globin silencing; and that let-7 controls the HIC2-BCL11A axis.

    Evidence Structural/biochemical oligomer analysis with engineered monomers; let-7 gain/loss-of-function with HIC2-BCL11A-HBG epistasis

    PMID:38364109 PMID:39607926

    Open questions at the time
    • identity of the corepressor surface engaged only by the tetramer not fully mapped
    • how oligomeric state intersects DNA binding not resolved
  13. 2024 High

    BCL11A is a multi-lineage transcriptional repressor with direct neural targets (Sema3c, Tbr1, Bcl6), an immune role in pDC commitment, and a defined neurodevelopmental disease through haploinsufficiency.

    Evidence Conditional knockouts with direct ChIP and rescue in cortical neurons; conditional KO of pDC lineage; human variant functional analysis with mouse modeling

    PMID:24591644 PMID:25972180 PMID:26182416 PMID:27453576 PMID:35766181

    Open questions at the time
    • shared vs lineage-specific corepressor usage across tissues not defined
    • whether the same TGACCA recognition operates at neural targets unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single repressor selects distinct target sets and corepressor complexes across erythroid, lymphoid, dendritic, and neural lineages remains unresolved.
  • lineage-specific cofactor codes not mapped
  • structural basis of TGACCA vs GGCCGG motif preference unresolved
  • integration of oligomeric state, DNA recognition, and corepressor choice not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2
Partners
BCL6CASKDNMT1GATA1LIN28BSIRT1SOX2SOX6
Complex memberships
BCL11A homotetramer (ZnF0-mediated)LSD1/CoREST corepressor complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 BCL11A is a developmental stage-specific repressor of fetal hemoglobin (HbF): full-length BCL11A isoforms are expressed in adult but not fetal erythroid cells, and BCL11A directly occupies multiple discrete sites in the beta-globin gene cluster. Knockdown of BCL11A in primary adult erythroid cells leads to robust HbF re-expression. ChIP occupancy at beta-globin locus; shRNA knockdown in primary adult erythroid cells; expression analysis of BCL11A isoforms across developmental stages Science High 19056937
2009 BCL11A is a critical mediator of species-divergent globin switching: developmental silencing of mouse embryonic globin and human gamma-globin genes fails to occur in BCL11A-null mice, demonstrating BCL11A is required in vivo for gamma-globin silencing. Bcl11a knockout mice; transgenic mice carrying human beta-globin locus; globin gene expression analysis across development Nature High 19657335
2010 BCL11A silences gamma-globin transcription via long-range chromosomal loop formation and physical/functional cooperation with SOX6. BCL11A binds the beta-globin locus control region (LCR), epsilon-globin, and intergenic regions between gamma- and delta-globin. BCL11A reconfigures the beta-globin cluster by modulating chromosomal loops, and co-occupies the cluster with SOX6 and GATA1. High-resolution ChIP-chip; chromosome conformation capture (3C) assay; co-immunoprecipitation of BCL11A and SOX6; knockdown in adult human erythroid progenitors Genes & Development High 20395365
2010 KLF1 directly activates BCL11A expression in adult erythroid progenitors, establishing a KLF1→BCL11A→gamma-globin repression axis. Knockdown of KLF1 markedly reduces BCL11A levels and increases gamma-globin/beta-globin expression ratios. KLF1 knockdown in human and mouse adult erythroid progenitors; gene expression analysis Nature Genetics High 20676097
2013 BCL11A is found within multiprotein complexes in erythroid cells consisting of erythroid transcription factors, transcriptional corepressors (LSD1/CoREST histone demethylase complex), and chromatin-modifying enzymes including DNMT1. LSD1/CoREST is required for full developmental silencing of gamma-globin, and DNMT1 is required to maintain HbF silencing in primary human adult erythroid cells. Proteomic screen of BCL11A-interacting proteins in erythroid cells; Co-IP; in vivo knockouts of LSD1 and DNMT1 combined with BCL11A deficiency; gene expression analysis PNAS High 23576758
2013 An erythroid-specific enhancer in BCL11A intron 2 (containing GATA1-binding sites) is required for BCL11A expression in erythroid but not B-lymphoid cells. Genome engineering deletion of this enhancer reduces BCL11A expression and de-represses HbF in an erythroid lineage-specific manner. Fine-mapping of GWAS variants; chromatin signature analysis; genome engineering (enhancer deletion) in erythroid and B-lymphoid cells; reporter assays; transgenic mice Science High 24115442
2015 Saturating mutagenesis of the BCL11A erythroid enhancer identifies critical minimal sequences and discrete functional vulnerabilities. The crucial human enhancer sequences are primate-specific despite conserved composite function. Editing of primary human progenitors and mouse transgenesis validate the enhancer as a target for HbF re-induction. Pooled CRISPR-Cas9 guide RNA library saturating mutagenesis; primary human progenitor editing; mouse transgenesis Nature High 26375006
2016 LRF/ZBTB7A represses HbF independently of BCL11A, through a NuRD repressor complex. LRF occupies fetal gamma-globin genes and maintains nucleosome density necessary for gamma-globin silencing; its mechanism is independent of BCL11A. ChIP; LRF/ZBTB7A knockdown in erythroid cells; epistasis between LRF and BCL11A pathways; NuRD complex interaction studies Science High 26816381
2018 BCL11A directly represses gamma-globin promoters through a specific zinc-finger cluster (ZF4-6) that recognizes a preferred DNA sequence (TGACCA motif) duplicated in gamma-globin promoters. BCL11A preferentially occupies the distal of two duplicated motifs (~-115 bp) in gamma-globin promoters; disruption of this motif by HPFH-associated mutations abrogates BCL11A binding and de-represses gamma-globin. Protein binding microarray; functional assay in erythroid cells; CUT&RUN chromatin occupancy mapping; CRISPR-Cas9 editing of promoter motifs; analysis of HPFH mutations Cell High 29606353
2018 Naturally occurring HPFH-associated point mutations at -115 bp and -200 bp in the gamma-globin promoter directly disrupt binding of BCL11A and ZBTB7A/LRF, respectively, establishing these as direct binding sites of major fetal globin repressors. CRISPR-Cas9 introduction of HPFH mutations into erythroid cells; ChIP/binding assays showing loss of repressor occupancy after mutation Nature Genetics High 29610478
2002 BCL11A (CTIP1) is a sequence-specific DNA binding protein that binds a GC-rich core motif (5'-GGCCGG-3') as an oligomeric complex and functions as a transcriptional repressor independently of COUP-TF family members. Repression is not reversed by trichostatin A (HDAC I/II inhibitor). In vitro DNA binding selection (SELEX); reporter gene repression assay; co-transfection experiments Biochemical Journal High 12196208
2005 BCL11A recruits SIRT1 (a class III HDAC) to a promoter template in a BCL11A-dependent manner, leading to deacetylation of histones H3 and/or H4 and transcriptional repression. BCL11A-mediated transcriptional repression is partially reversed by nicotinamide (SIRT1 inhibitor) but not trichostatin A (class I/II HDAC inhibitor). BCL11A and SIRT1 interact directly. Chromatin immunoprecipitation (ChIP); co-immunoprecipitation; nicotinamide/trichostatin A pharmacological inhibition; reporter gene assays in mammalian cells Archives of Biochemistry and Biophysics Medium 15639232
2003 Bcl11a is essential for postnatal development and normal lymphopoiesis: Bcl11a-null mice lack B cells and have alterations in T cells. Bcl11a functions upstream of transcription factors Ebf1 and Pax5 in the B cell developmental pathway, and these defects are intrinsic to hematopoietic precursor cells. Bcl11a knockout mice; transplantation studies with Bcl11a-deficient fetal liver cells; phenotypic and expression analysis of Ebf1 and Pax5 Nature Immunology High 12717432
2006 BCL11A-XL is a DNA sequence-specific transcriptional repressor that associates with itself and other BCL11A isoforms, as well as with the BCL6 proto-oncogene. BCL11A-XL/BCL6 interaction can modulate BCL6 DNA binding in vitro. BCL11A-XL partitions into the nuclear matrix and colocalizes with BCL6 in nuclear paraspeckles of germinal center B cells. Co-immunoprecipitation; Western blot; in vitro DNA binding assay; subcellular fractionation; immunofluorescence/co-localization Molecular Cancer Medium 16704730
2012 Bcl11a is essential for lymphopoiesis in adult mice and negatively regulates p53: Bcl11a deletion causes apoptosis in early B cells and CLPs and abolishes lymphoid development of HSCs. Bcl11a regulates expression of Bcl2, Bcl2-xL, and Mdm2 (p53 inhibitor); overexpression of Bcl2 and Mdm2, or p53 deficiency, rescues lethality and proliferative defects in Bcl11a-deficient early B cells. Conditional Bcl11a deletion in adult mice; rescue experiments with Bcl2, Mdm2 overexpression and p53 knockout; gene expression analysis Journal of Experimental Medicine High 23230003
2009 BCL11A directly represses HBG (gamma-globin) transcription in K562 cells by binding to a GGCCGG motif at nucleotides -56 to -51 on the HBG proximal promoter. BCL11A overexpression reduces HBG promoter transcriptional activity by >50%; this is abrogated by sodium butyrate. Luciferase reporter assay; BCL11A overexpression by transfection; ChIP/DNA binding to HBG promoter Blood Cells, Molecules & Diseases Medium 19153051
2014 BCL11A is required for plasmacytoid dendritic cell (pDC) development: embryonic deletion of Bcl11a results in complete absence of pDCs, and conditional adult deletion eliminates pDC and B-cell lineages while sparing myeloid, conventional DC, and T-cell lineages. BCL11A regulates transcription of E2-2 and pDC differentiation modulators including ID2 and MTG16. Embryonic germ-line and conditional Bcl11a deletion; genome-wide BCL11A ChIP and expression analysis; viral challenge experiments PNAS High 24591644
2015 Bcl11a (Ctip1) controls polarity and migration of upper-layer cortical projection neurons by directly repressing Sema3c transcription. Bcl11a-deficient neurons fail to switch from multipolar to bipolar morphology and show impaired radial migration; Sema3c overexpression is required for these defects and in vivo rescue with Sema3c reduction restores normal migration. Conditional Bcl11a knockout in cortical neurons; gain-of-function and rescue experiments in vivo; ChIP demonstrating direct Bcl11a binding to Sema3c regulatory region; live imaging of migration Neuron High 26182416
2012 Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord. Loss of Bcl11a disrupts terminal differentiation and morphogenesis of dorsal spinal neurons and their innervation by cutaneous sensory neurons. Bcl11a regulates sFRP3/Frzb expression, and Frzb loss phenocopies the innervation deficit. Bcl11a knockout mice; gene expression profiling of dorsal horn; Frzb mutant analysis; genetic epistasis Development High 22491945
2015 Ctip1/BCL11A regulates subtype identity of deep-layer cortical projection neurons: loss of Ctip1 causes a bias toward subcerebral projection neuron development at the expense of corticothalamic and deep-layer callosal neurons. Misexpression of Ctip1 in vivo represses subcerebral gene expression and projections. Ctip1 conditional KO and overexpression in mice; layer-type-specific projection neuron markers; axonal tracing Cell Reports High 27117402
2015 Ctip1 controls acquisition of sensory area identity and establishment of sensory input fields in the neocortex by repressing motor and activating sensory programs of gene expression, enabling layer IV neuron differentiation required for thalamocortical axon organization. Ctip1 conditional KO in cortex; gene expression profiling; thalamocortical axon tracing; cortical area marker analysis Neuron High 27100196
2015 CTIP1/BCL11A directly represses Tbr1 transcription in layer 5 cortical neurons; this repression is a critical step for acquisition of subcerebral fate. Lower CTIP1 levels in layer 6 are required for TBR1 expression, which directs corticothalamic fate, demonstrating that differential CTIP1 dosage specifies distinct corticofugal identities. ChIP demonstrating direct CTIP1 binding to Tbr1 regulatory region; conditional KO and overexpression in mice; corticofugal projection analysis Journal of Neuroscience High 25972180
2009 Bcl11A-L controls axon branching and dendrite outgrowth by regulating expression of DCC and MAP1b. Bcl11A-L knockdown induces axon branching and multi-axon formation; DCC overexpression rescues the Bcl11A-L knockdown phenotype. Bcl11A-S acts as an antagonist of Bcl11A-L. shRNA knockdown in cultured neurons; time-lapse imaging; DCC rescue experiments; gene expression analysis Molecular and Cellular Neurosciences Medium 19616629
2010 CASK (X-linked mental retardation gene) interacts with both Bcl11A-L and Bcl11A-S isoforms; the interaction colocalizes in neuronal nuclei in vivo. CASK enhances Bcl11A-L's ability to restrict axon outgrowth and branching; disruption of the CASK–Bcl11A interaction increases axon arborization. Bcl11A-L also rearranges nuclear actin distribution. Yeast two-hybrid screen; co-immunoprecipitation from COS cells and brain; immunofluorescence co-localization; disruption of interaction in hippocampal neurons; axon branching assays Journal of Neuroscience Research Medium 20623620
2012 BCL11A interacts with the orphan nuclear receptor TLX (NR2E1) and potentiates its transrepressive function in reporter gene assays. Interaction validated by co-immunoprecipitation in human cells. Yeast two-hybrid screen of human brain cDNA library; co-immunoprecipitation in human cells; in vitro reporter gene assay PLoS ONE Low 22675500
2016 Bcl11a deficiency in adult mice leads to HSC defects with aging-like phenotypes, including downregulation of CDK6 and cell-cycle delay, correlating with HSC dysfunction and exhaustion. Conditional Bcl11a deletion in adult mice; HSC transplantation; cell-cycle analysis; CDK6 expression analysis Cell Reports Medium 27653684
2016 BCL11A haploinsufficiency-causing missense mutations cluster in the amino-terminal region and disrupt BCL11A localization, dimerization, and transcriptional regulatory activity, consistent with loss of function. Mouse Bcl11a haploinsufficiency causes impaired cognition, abnormal social behavior, and microcephaly. Human cellular analyses; mouse behavioral phenotyping; neuroanatomical analysis; transcriptional profiling of cortex and hippocampus; functional assays of BCL11A variants American Journal of Human Genetics High 27453576
2020 BCL11A is regulated at the level of mRNA translation during human hematopoietic development. The RNA-binding protein LIN28B (developmentally expressed reciprocal to BCL11A) directly interacts with ribosomes and BCL11A mRNA to suppress its translation independently of its role in regulating let-7 microRNAs. BCL11A is the major target of LIN28B-mediated HbF induction. Unbiased genomic and proteomic analyses; ribosome profiling; LIN28B–BCL11A mRNA interaction studies; rescue experiments with let-7-resistant BCL11A constructs Nature Genetics High 31959994
2020 The transcription factor ATF4, regulated downstream of the eIF2α kinase HRI, directly stimulates BCL11A transcription by binding to the BCL11A erythroid enhancer and fostering enhancer-promoter contacts, establishing a linear HRI→ATF4→BCL11A→gamma-globin pathway. CRISPR-Cas9-guided loss-of-function screen in human erythroblasts; ChIP showing ATF4 binding to BCL11A enhancer; chromatin conformation analysis; HRI-deficient mice Blood High 32299090
2022 HIC2 represses BCL11A transcription by binding to erythroid BCL11A enhancers, reducing chromatin accessibility and GATA1 binding, diminishing enhancer activity and enhancer-promoter contacts. Crystallography reveals that HIC2 causes direct steric hindrance of GATA1 binding at a critical BCL11A enhancer. HIC2 and BCL11A are reciprocally expressed during development. ChIP; ATAC-seq; chromosome conformation capture; DNA binding studies; X-ray crystallography; HIC2 forced expression and loss-of-function in erythroblasts Nature Genetics High 35941187
2024 BCL11A forms a tetramer in erythroid cells mediated by a single N-terminal zinc finger (ZnF0). Tetramer formation is required for steady-state BCL11A protein production (protein stability), and the tetramer state is necessary for gamma-globin gene repression because an engineered BCL11A monomer fails to engage a critical co-repressor complex. Biochemical and structural analysis of BCL11A oligomeric state; engineered monomer constructs; co-repressor complex engagement assays; fetal hemoglobin expression assays in erythroid cells Science High 39607926
2022 Upon acute BCL11A protein depletion in erythroid cells (using dTAG PROTAC), HBG1/2 transcriptional re-activation occurs within <2 hours and is followed by increased chromatin accessibility; both are uncoupled from promoter DNA methylation changes at HBG1/2 loci. Among 31 BCL11A-repressed genes, HBG1/2 and HBZ show the most abundant changes. dTAG PROTAC-mediated acute BCL11A degradation; nascent transcriptomics; proteomics; ATAC-seq; histone profiling; DNA methylation analysis Cell Chemical Biology High 35839780
2021 Pathogenic BCL11A missense variants in an N-terminal C2HC zinc finger cause increased proteasomal degradation of BCL11A, leading to loss of HbF silencing. A distinct C-terminal missense variant in the fifth zinc finger domain causes loss-of-function through disruption of DNA binding. Functional studies in erythroid cells; proteasome inhibitor experiments; DNA binding assays for zinc finger variants PLoS Genetics Medium 34634037
2022 BCL11A promotes myeloid leukemogenesis by repressing PU.1 target genes (including Asb2, Clec5a, Fcgr3) through sequence-specific DNA binding and recruitment of corepressors (HDAC and LSD1). Corepressor inhibition (HDAC inhibitor pracinostat and LSD1 inhibitor GSK2879552) reverses BCL11A-mediated repression and inhibits AML growth in vitro and in vivo. ChIP-seq in AML cells; co-culture and engraftment models; pharmacological HDAC/LSD1 inhibition; BCL11A knockdown in HL-60 cells Blood Advances Medium 34714913
2018 BCL11A interacts with SOX2 and is required for its oncogenic functions in lung squamous cell carcinoma (LUSC). BCL11A and SOX2 together regulate expression of epigenetic regulators including SETD8; SETD8 inhibition selectively inhibits LUSC growth. Co-immunoprecipitation of BCL11A and SOX2; shRNA knockdown and overexpression in vitro and in vivo xenograft; gene expression profiling; pharmacological SETD8 inhibition Nature Communications Medium 30127402
2018 BCL11A interacts with DNMT1 in TNBC cells (co-immunoprecipitation). BCL11A-DNMT1 interaction sustains cancer stemness and tumorigenesis; silencing of either BCL11A or DNMT1 impairs cancer stemness via suppressing ISL1 expression. miR-137 suppresses this pathway by targeting BCL11A 3'UTR. Co-immunoprecipitation; luciferase reporter assay for miR-137/BCL11A interaction; shRNA knockdown; mammosphere and xenograft assays Cellular Physiology and Biochemistry Low 29975921
2022 Bcl11a is a direct transcriptional regulator of Bcl6 in cortical projection neurons. Loss of Bcl11a in cortical neurons causes pronounced cell death in upper-layer neurons. Deletion of Bcl6 also causes cortical neuron death, while reintroduction of Bcl6 into Bcl11a mutants rescues cell death, establishing a Bcl11a→Bcl6 anti-apoptotic pathway in corticogenesis. Conditional Bcl11a and Bcl6 knockout mice; ChIP showing direct Bcl11a binding to Bcl6 regulatory region; Bcl6 rescue experiments in Bcl11a mutants EMBO Reports High 35766181
2021 BCL11A defines distinct subsets of midbrain dopaminergic (mDA) neurons forming a specific subcircuit in the murine dopaminergic system. In the substantia nigra, BCL11A-expressing mDA neurons are particularly vulnerable to neurodegeneration upon alpha-synuclein overexpression or oxidative stress. Bcl11a inactivation in mDA neurons increases this vulnerability, alters their distribution, and results in skilled motor deficits. Intersectional labeling and viral-mediated axonal tracing; conditional Bcl11a knockout in mDA neurons; alpha-synuclein overexpression model; behavioral analysis Cell Reports High 34525371
2023 Nanobodies directed to a region of BCL11A comprising zinc fingers 4–6 (ZF456), specifically ZF6, mediate targeted protein degradation of BCL11A in erythroid cells and reactivate HbF. The nanobodies distinguish BCL11A from its close paralog BCL11B despite identical DNA-binding specificity. Yeast surface display nanobody selection; structural determination; molecular modeling; nanobody-mediated targeted protein degradation in erythroid cells; HbF expression assay PNAS High 36626555
2024 The let-7 miRNA family directly represses HIC2 (a BCL11A transcriptional repressor) post-transcriptionally in adult erythroblasts. Loss of global miRNA biogenesis via DICER1 depletion upregulates HIC2 and HBG mRNA. Ectopic let-7 in fetal cells lowers HIC2; inhibition of let-7 in adult erythroblasts increases HIC2, decommissions the BCL11A erythroid enhancer, and reduces BCL11A transcription. HIC2 depletion in let-7-inhibited cells restores BCL11A-mediated HBG repression. DICER1 depletion; let-7 overexpression and inhibition in erythroid cells; epistasis between let-7, HIC2, BCL11A, and HBG expression; ChIP/ATAC of BCL11A enhancer Blood High 38364109
2017 BCL11A (CTIP1) is highly expressed in the developing murine epidermis and is required for epidermal permeability barrier establishment. Ctip1 deletion causes compromised epidermal differentiation, reduced profilaggrin processing, and altered lipid composition. CTIP1 directly occupies regulatory regions of Fosl2 and Elovl4 (lipid metabolism) genes. Germline Ctip1 knockout mice; transcriptional profiling; ChIP at Fosl2 and Elovl4 regulatory regions; epidermal barrier functional assays Scientific Reports Medium 29044125
2013 Bcl11a controls Flt3 and IL-7 receptor expression in early hematopoietic progenitors, and is required for pDC development. Bcl11a-null cells show severely impaired Flt3L-derived pDC and cDC development in vitro, but normal GM-CSF-driven DC development, demonstrating a Flt3-dependent requirement. Bcl11a knockout fetal liver chimeras; in vitro DC differentiation with Flt3L vs. GM-CSF; gene expression analysis in progenitors PLoS ONE Medium 23741395
2013 Double knockdown of BCL11A and DNMT1 in MEL cells enhances gamma-globin expression cooperatively (up to 90% of total beta-like globin species), while double knockdown of Myb and DNMT1 robustly induces epsilon-globin, demonstrating that BCL11A and Myb cooperate with DNMT1 to achieve developmental repression of fetal/embryonic beta-like globin genes. RNAi knockdown (single and double) in MEL cells carrying human beta-globin locus fluorescent reporters; qRT-PCR; DsRed/eGFP reporter quantification FASEB Journal Medium 24371119
2007 In rat brain, Bcl11A-L is enriched at the postsynaptic density (PSD I and II fractions) and both Bcl11A-L and Bcl11A-S isoforms are found in extranuclear and synaptic locations in addition to neuronal nuclei, as determined by biochemical fractionation and confocal co-localization with synaptophysin. Biochemical fractionation (PSD purification); immunoblotting; immunofluorescence co-localization with synaptic markers Journal of Neuroscience Research Medium 17455301

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science (New York, N.Y.) 764 19056937
2015 BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 717 26375006
2013 An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science (New York, N.Y.) 531 24115442
2008 DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proceedings of the National Academy of Sciences of the United States of America 456 18667698
2018 Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch. Cell 392 29606353
2020 Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. The New England journal of medicine 336 33283990
2009 Developmental and species-divergent globin switching are driven by BCL11A. Nature 328 19657335
2010 KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nature genetics 320 20676097
2016 Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science (New York, N.Y.) 309 26816381
2010 Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes & development 309 20395365
2003 Bcl11a is essential for normal lymphoid development. Nature immunology 280 12717432
2001 The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Blood 261 11719382
2018 Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nature genetics 247 29610478
2013 Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proceedings of the National Academy of Sciences of the United States of America 196 23576758
2012 Bcl11a is essential for lymphoid development and negatively regulates p53. The Journal of experimental medicine 184 23230003
2008 BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood cells, molecules & diseases 155 18691915
2022 CRISPR-Cas9-mediated gene editing of the BCL11A enhancer for pediatric β0/β0 transfusion-dependent β-thalassemia. Nature medicine 138 35922667
2016 Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. The Journal of clinical investigation 136 27599293
2016 BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription. American journal of human genetics 132 27453576
2004 CTIP1 and CTIP2 are differentially expressed during mouse embryogenesis. Gene expression patterns : GEP 132 15465497
2015 BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations. The Journal of clinical investigation 131 25938782
2002 COUP-TF (chicken ovalbumin upstream promoter transcription factor)-interacting protein 1 (CTIP1) is a sequence-specific DNA binding protein. The Biochemical journal 126 12196208
2015 BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells. Nature communications 120 25574598
2015 Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin. Current opinion in genetics & development 109 26375765
2013 MicroRNA-486-3p regulates γ-globin expression in human erythroid cells by directly modulating BCL11A. PloS one 106 23593217
2016 Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype. Cell reports 103 27653684
2015 miRNA-embedded shRNAs for Lineage-specific BCL11A Knockdown and Hemoglobin F Induction. Molecular therapy : the journal of the American Society of Gene Therapy 100 26080908
2014 Dendritic cell fate is determined by BCL11A. Proceedings of the National Academy of Sciences of the United States of America 99 24591644
2020 Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation. Nature genetics 93 31959994
2015 Bcl11a (Ctip1) Controls Migration of Cortical Projection Neurons through Regulation of Sema3c. Neuron 89 26182416
2015 Single-cell transcriptomic reconstruction reveals cell cycle and multi-lineage differentiation defects in Bcl11a-deficient hematopoietic stem cells. Genome biology 89 26387834
2006 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. Molecular cancer 80 16704730
2014 Association of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in Cameroon. PloS one 74 24667352
2020 The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression. Blood 66 32299090
2012 Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord development. Development (Cambridge, England) 64 22491945
2014 De novo microdeletion of BCL11A is associated with severe speech sound disorder. American journal of medical genetics. Part A 62 24810580
2016 Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers. Cell reports 59 27117402
2020 BCL11A enhancer-edited hematopoietic stem cells persist in rhesus monkeys without toxicity. The Journal of clinical investigation 58 32897878
2020 Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. Molecular therapy. Methods & clinical development 57 32300607
2019 BCL11A: a potential diagnostic biomarker and therapeutic target in human diseases. Bioscience reports 57 31654056
2009 Bcl11A/CTIP1 regulates expression of DCC and MAP1b in control of axon branching and dendrite outgrowth. Molecular and cellular neurosciences 56 19616629
2005 BCL11A-dependent recruitment of SIRT1 to a promoter template in mammalian cells results in histone deacetylation and transcriptional repression. Archives of biochemistry and biophysics 55 15639232
2019 Targeted deletion of BCL11A gene by CRISPR-Cas9 system for fetal hemoglobin reactivation: A promising approach for gene therapy of beta thalassemia disease. European journal of pharmacology 53 31039344
2018 BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma. Nature communications 53 30127402
2016 Ctip1 Controls Acquisition of Sensory Area Identity and Establishment of Sensory Input Fields in the Developing Neocortex. Neuron 53 27100196
2010 Binding patterns of BCL11A in the globin and GATA1 loci and characterization of the BCL11A fetal hemoglobin locus. Blood cells, molecules & diseases 52 20542454
2009 BCL11A represses HBG transcription in K562 cells. Blood cells, molecules & diseases 52 19153051
2020 Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin. Scientific reports 49 32576837
2016 Hydroxyurea down-regulates BCL11A, KLF-1 and MYB through miRNA-mediated actions to induce γ-globin expression: implications for new therapeutic approaches of sickle cell disease. Clinical and translational medicine 49 27056246
2015 The Specification of Cortical Subcerebral Projection Neurons Depends on the Direct Repression of TBR1 by CTIP1/BCL11a. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 25972180
2013 BCL11A overexpression predicts survival and relapse in non-small cell lung cancer and is modulated by microRNA-30a and gene amplification. Molecular cancer 48 23758992
2014 Induction of adult levels of β-globin in human erythroid cells that intrinsically express embryonic or fetal globin by transduction with KLF1 and BCL11A-XL. Haematologica 47 25107887
2013 Bcl11a controls Flt3 expression in early hematopoietic progenitors and is required for pDC development in vivo. PloS one 47 23741395
2016 Regulation of the fetal hemoglobin silencing factor BCL11A. Annals of the New York Academy of Sciences 46 26963603
2018 MiR-137 Suppresses Triple-Negative Breast Cancer Stemness and Tumorigenesis by Perturbing BCL11A-DNMT1 Interaction. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 45 29975921
2013 Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice. Blood 45 23361909
2022 HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription. Nature genetics 44 35941187
2016 Strict in vivo specificity of the Bcl11a erythroid enhancer. Blood 44 27707736
2022 Single-cell deletion analyses show control of pro-T cell developmental speed and pathways by Tcf7, Spi1, Gata3, Bcl11a, Erg, and Bcl11b. Science immunology 42 35594339
2013 Transcriptional regulators Myb and BCL11A interplay with DNA methyltransferase 1 in developmental silencing of embryonic and fetal β-like globin genes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 24371119
2010 X-linked mental retardation gene CASK interacts with Bcl11A/CTIP1 and regulates axon branching and outgrowth. Journal of neuroscience research 37 20623620
2020 miR‑574‑5p attenuates proliferation, migration and EMT in triple‑negative breast cancer cells by targeting BCL11A and SOX2 to inhibit the SKIL/TAZ/CTGF axis. International journal of oncology 35 32319565
2022 Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells. Cell chemical biology 34 35839780
2016 Inhibition of FOXQ1 induces apoptosis and suppresses proliferation in prostate cancer cells by controlling BCL11A/MDM2 expression. Oncology reports 34 27573292
2015 BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia. Blood cells, molecules & diseases 33 25703683
2014 DNA polymorphisms at BCL11A, HBS1L-MYB and Xmn1-HBG2 site loci associated with fetal hemoglobin levels in sickle cell anemia patients from Northern Brazil. Blood cells, molecules & diseases 33 25084696
2019 BCL11A enhances stemness and promotes progression by activating Wnt/β-catenin signaling in breast cancer. Cancer management and research 32 31114347
2010 Bcl11A/CTIP1 mediates the effect of the glutamate receptor on axon branching and dendrite outgrowth. Journal of neurochemistry 29 20534004
2022 BCL11A promotes myeloid leukemogenesis by repressing PU.1 target genes. Blood advances 28 34714913
2022 Transcription factors Bcl11a and Bcl11b are required for the production and differentiation of cortical projection neurons. Cerebral cortex (New York, N.Y. : 1991) 27 34963132
2019 Long noncoding RNA DSCAM-AS1 functions as an oncogene in non-small cell lung cancer by targeting BCL11A. European review for medical and pharmacological sciences 27 30779076
2012 The oncoprotein BCL11A binds to orphan nuclear receptor TLX and potentiates its transrepressive function. PloS one 27 22675500
2017 Identification of novel BCL11A variants in patients with epileptic encephalopathy: Expanding the phenotypic spectrum. Clinical genetics 26 28589569
2016 Modifying effect of XmnI, BCL11A, and HBS1L-MYB on clinical appearances: A study on β-thalassemia and hemoglobin E/β-thalassemia patients in Indonesia. Hematology/oncology and stem cell therapy 26 27009595
2017 BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems. American journal of medical genetics. Part A 24 28960836
2021 The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons. Cell reports 23 34525371
2017 Transcription Factor CTIP1/ BCL11A Regulates Epidermal Differentiation and Lipid Metabolism During Skin Development. Scientific reports 23 29044125
2023 Evolution of nanobodies specific for BCL11A. Proceedings of the National Academy of Sciences of the United States of America 22 36626555
2019 Long noncoding RNA CDKN2B-AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 30870006
2017 Haploinsufficiency of BCL11A associated with cerebellar abnormalities in 2p15p16.1 deletion syndrome. Molecular genetics & genomic medicine 22 28717667
2016 The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil. Blood cells, molecules & diseases 22 27838552
2014 Genotyping of BCL11A and HBS1L-MYB SNPs associated with fetal haemoglobin levels: a SNaPshot minisequencing approach. BMC genomics 22 24502199
2020 miR-30a regulates γ-globin expression in erythoid precursors of intermedia thalassemia through targeting BCL11A. Molecular biology reports 21 32406020
2020 The transcriptional repressor BCL11A promotes breast cancer metastasis. The Journal of biological chemistry 21 32576660
2007 Expression of zinc finger transcription factor Bcl11A/Evi9/CTIP1 in rat brain. Journal of neuroscience research 20 17455301
2021 Pathogenic BCL11A variants provide insights into the mechanisms of human fetal hemoglobin silencing. PLoS genetics 19 34634037
2020 BCL11A Promotes the Progression of Laryngeal Squamous Cell Carcinoma. Frontiers in oncology 19 32266150
2020 Functional polymorphisms of BCL11A and HBS1L-MYB genes affect both fetal hemoglobin level and clinical outcomes in a cohort of children with sickle cell anemia. Annals of hematology 19 32447424
2015 Variation in Gamma-Globin Expression before and after Induction with Hydroxyurea Associated with BCL11A, KLF1 and TAL1. PloS one 19 26053062
2022 CRISPR/Cas9-based multiplex genome editing of BCL11A and HBG efficiently induces fetal hemoglobin expression. European journal of pharmacology 17 35093321
2024 A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing. Science (New York, N.Y.) 16 39607926
2022 Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6-dependent pathway. EMBO reports 16 35766181
2022 MicroRNA-92a-3p-mediated inhibition of BCL11A upregulates γ-globin expression and inhibits oxidative stress and apoptosis in erythroid precursor cells. Hematology (Amsterdam, Netherlands) 16 36178486
2018 miR-146a induces apoptosis in neuroblastoma cells by targeting BCL11A. Medical hypotheses 16 30077189
2014 BCL11A gene DNA methylation contributes to the risk of type 2 diabetes in males. Experimental and therapeutic medicine 16 25009601
2024 let-7 miRNAs repress HIC2 to regulate BCL11A transcription and hemoglobin switching. Blood 15 38364109
2021 Molecular analysis of the erythroid phenotype of a patient with BCL11A haploinsufficiency. Blood advances 15 33938942
2019 Molecular simulation studies on B-cell lymphoma/leukaemia 11A (BCL11A). American journal of translational research 15 31312380
2017 Genetic polymorphisms and plasma levels of BCL11A contribute to the development of laryngeal squamous cell carcinoma. PloS one 15 28225775
2015 BCL11A expression in acute myeloid leukemia. Leukemia research 15 26707798

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