Affinage

NIPBL

Nipped-B-like protein · UniProt Q6KC79

Length
2804 aa
Mass
316.1 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NIPBL is the obligate activating subunit of the cohesin loader that stimulates cohesin's ATPase to drive topological DNA entrapment and processive DNA loop extrusion, thereby shaping three-dimensional genome architecture and transcriptional output (PMID:32409525, PMID:35476527). Cryo-EM shows NIPBL and DNA together promote engagement of cohesin's ATPase head domains and form a central tunnel that entraps DNA, with the cohesin hinge docking onto STAG1 to explain synergistic activation (PMID:32409525); high-speed AFM and quantitative in vitro reconstitution further establish that NIPBL acts as a tight DNA anchor during the mechanochemical loop extrusion cycle, with DNA capture and loop initiation occurring independently of ATP hydrolysis (PMID:37774974, PMID:40763028). NIPBL partners with MAU2 as a heterodimer, yet an N-terminally truncated NIPBL lacking the MAU2-binding region still binds DNA and loads cohesin, showing cohesin loading can proceed without a functional NIPBL/MAU2 heterodimer (PMID:32433956). Beyond cohesin loading, NIPBL functions as a direct transcriptional regulator: it binds active promoters with distinct timing and high affinity and regulates their expression in a cohesin-independent manner (PMID:24550742), recruits HDAC1/HDAC3 through a conserved region mutated in CdLS to repress promoters (PMID:18854353), and is targeted to enhancers and promoters via interactions with BRD4, the glucocorticoid receptor, Zfp609/Integrator, and chromatin remodelers and acetyltransferases (P300/CBP, BRG1/BRM) (PMID:29379197, PMID:31320616, PMID:28041881, PMID:33334824, PMID:35353576). NIPBL and WAPL act as opposing cohesin regulators whose balance controls gene expression, and acute degron studies show NIPBL preferentially supports super-enhancer contacts and cell-identity gene programs (PMID:36449519, PMID:36449618, PMID:41699137). NIPBL additionally promotes NHEJ during double-strand break repair through HP1γ- and RNF8/RNF168-dependent recruitment to break sites (PMID:28167679, PMID:24145515), and modulates RNA processing to prevent activation of the stress kinase PKR (PMID:26725122). Haploinsufficiency of NIPBL causes Cornelia de Lange syndrome, and CdLS-associated missense mutations impair both loop extrusion activity and HDAC recruitment, indicating that the disorder arises chiefly from cumulative transcriptional dysregulation rather than failure of sister chromatid cohesion (PMID:35476527, PMID:18854353, PMID:23920377).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2008 High

    Established the first cohesin-independent biochemical activity of NIPBL by showing it directly engages histone deacetylases to repress transcription, linking NIPBL physically to chromatin modification.

    Evidence Yeast two-hybrid, Co-IP, and GAL4 reporter assays mapping HDAC1/HDAC3 binding to a CdLS-mutated 163-aa region

    PMID:18854353

    Open questions at the time
    • Genome-wide targets of NIPBL-HDAC repression not defined
    • Did not address relationship to cohesin loading function
  2. 2009 Medium

    Connected NIPBL mutation to genome-wide transcriptional dysregulation by showing cohesin occupies cis-regulatory and promoter regions of dysregulated genes in CdLS patient cells.

    Evidence Transcriptional profiling of 16 CdLS cell lines and cohesin ChIP-seq

    PMID:19468298

    Open questions at the time
    • Correlative association between cohesin occupancy and dysregulation
    • Did not separate NIPBL loading function from direct transcriptional roles
  3. 2011 Medium

    Defined a damage-response role for NIPBL by demonstrating it is recruited to double-strand breaks via the MDC1/RNF168/HP1γ axis.

    Evidence Immunofluorescence at microirradiation and I-PpoI breaks with RNAi of damage factors

    PMID:21784059

    Open questions at the time
    • Single-method per component
    • Functional consequence of recruitment for repair not tested here
  4. 2013 High

    Distinguished NIPBL's developmental relevance from cohesion by showing Nipbl haploinsufficiency leaves bulk cohesion and replication intact while selectively reducing cohesin at specific promoters.

    Evidence Cohesion, replication, repair, segregation assays plus locus ChIP and expression in Nipbl+/- mouse cells

    PMID:23920377

    Open questions at the time
    • Mechanism of locus-specific cohesin loss unresolved
    • Did not address loop extrusion directly
  5. 2013 High

    Established an evolutionarily conserved role for NIPBL in non-homologous end joining and DSB repair pathway choice, distinct from its cohesion function.

    Evidence CSR junction analysis in patient B cells, plasmid end-joining assay, yeast NHEJ model, 53BP1 recruitment

    PMID:24145515

    Open questions at the time
    • Direct molecular link between NIPBL and 53BP1 recruitment unclear
    • Quantitative contribution to repair fidelity not measured
  6. 2013 Medium

    Provided independent evidence that NIPBL shapes chromatin architecture by showing its loss decompacts gene-rich chromatin without phenocopying cohesin or CTCF loss.

    Evidence FISH in CdLS patient and siRNA-depleted cells comparing NIPBL, SMC3, and CTCF knockdowns

    PMID:23760082

    Open questions at the time
    • Molecular basis of cohesin-independent decompaction undefined
    • Single lab
  7. 2014 High

    Demonstrated a cohesin-independent transcriptional function by mapping high-affinity NIPBL binding to active promoters with distinct timing from cohesin.

    Evidence ChIP-seq with comparative NIPBL versus cohesin knockdown and expression analysis

    PMID:24550742

    Open questions at the time
    • Molecular mechanism by which NIPBL regulates promoter transcription not resolved
    • Recruitment determinants at promoters unidentified here
  8. 2016 High

    Linked NIPBL to neuronal development via a cohesin-independent interaction with Zfp609 and the Integrator complex at paused Pol II promoters.

    Evidence Co-IP, MS, ChIP-seq, and in vivo cortical knockdown with neuronal migration readout

    PMID:28041881

    Open questions at the time
    • Whether Integrator/pause-release control is direct NIPBL output not fully resolved
    • Connection to CdLS neurology indirect
  9. 2017 High

    Resolved that NIPBL binds chromatin chiefly through cohesin and moves between cohesin rings, indicating a post-loading rather than purely loading function.

    Evidence FRAP and single-molecule tracking in live human cells

    PMID:28914604

    Open questions at the time
    • Functional purpose of hopping behavior not defined
    • Relationship to loop extrusion dynamics untested here
  10. 2017 High

    Dissected two independent NIPBL DSB-recruitment routes, separating an N-terminal HP1γ-dependent mechanism from a C-terminal HEAT-repeat, ATM/ATR-dependent mechanism, both requiring RNF8/RNF168.

    Evidence Live-cell imaging at laser microirradiation, RNAi, and domain mutagenesis

    PMID:28167679

    Open questions at the time
    • Downstream repair outcome of each route not quantified
    • Interplay between the two recruitment modes unclear
  11. 2018 High

    Identified BRD4 as a NIPBL partner co-regulating developmental genes at super-enhancers, and discriminated CdLS-like BRD4 variants by retained NIPBL binding.

    Evidence Co-IP, ChIP-seq, and patient-variant functional analysis

    PMID:29379197

    Open questions at the time
    • Whether BRD4 recruits NIPBL or vice versa not settled here
    • Cohesin dependence of co-regulation not separated
  12. 2019 High

    Mapped the direct NIPBL-BRD4 interaction to the BRD4 ET domain and showed mutual stabilization at promoters with conserved functional cooperation across species.

    Evidence Yeast interaction, Co-IP, ChIP-seq, RNA-seq, and Drosophila epistasis

    PMID:31320616

    Open questions at the time
    • Quantitative contribution of BRD4 to NIPBL chromatin residence not measured
    • Cohesin loading dependence not addressed
  13. 2020 High

    Provided the structural mechanism of cohesin activation, showing NIPBL and DNA together engage cohesin ATPase heads and form a DNA-entrapping tunnel with the hinge docked on STAG1.

    Evidence Cryo-EM of human cohesin-NIPBL-DNA

    PMID:32409525

    Open questions at the time
    • Static structure; dynamics of the extrusion cycle inferred
    • Did not capture transcription-factor-bound states
  14. 2020 High

    Showed signal-responsive NIPBL recruitment with distinct enhancer versus promoter logic, requiring P300/CBP and BRG1/BRM at enhancers but GC-rich sequence at promoters.

    Evidence ChIP-seq with acute NIPBL degradation and depletion of acetyltransferases/remodelers under calcium signaling

    PMID:33334824

    Open questions at the time
    • Direct versus indirect dependence on remodelers not fully separated
    • Transcriptional consequences of recruitment not quantified here
  15. 2020 High

    Decoupled cohesin loading from the NIPBL/MAU2 heterodimer by showing a MAU2-binding-deficient NIPBL form still loads cohesin.

    Evidence Engineered NIPBL truncation cell lines, reciprocal Co-IP, and cohesin loading assay

    PMID:32433956

    Open questions at the time
    • Physiological role of MAU2 if not required for loading unclear
    • Quantitative loading efficiency without MAU2 not benchmarked
  16. 2022 High

    Linked CdLS pathology directly to loop extrusion by showing disease missense mutations impair NIPBL-dependent in vitro loop extrusion.

    Evidence In vitro DNA loop extrusion assays with CdLS mutant NIPBL

    PMID:35476527

    Open questions at the time
    • In vivo TAD/enhancer consequences of these mutants not measured
    • Range of mutant phenotypes incompletely sampled
  17. 2022 Medium

    Established that NIPBL and WAPL are opposing cohesin regulators whose balance sets gene expression, in cells and in vivo.

    Evidence Combinatorial siRNA with RNA-seq in HCT116 and Nipbl/Wapl double-heterozygote mouse epistasis

    PMID:36449519 PMID:36449618

    Open questions at the time
    • Mechanism of mutual rescue at individual loci not resolved
    • Single lab per system
  18. 2022 High

    Connected NIPBL/cohesin to ligand-dependent transcription by showing the glucocorticoid receptor interacts with NIPBL to promote loop extrusion and long-range regulation.

    Evidence Mass spectrometry, ChIP-seq, single-molecule tracking, and cohesin depletion

    PMID:35353576

    Open questions at the time
    • Direct GR-NIPBL contact interface not structurally defined here
    • Generalization to other nuclear receptors untested in this study
  19. 2024 Medium

    Implicated NIPBL in transcriptional control of cohesin and growth genes via recruitment of the demethylase KDM6B and antagonism of EZH2.

    Evidence ChIP, MeRIP, RNA decay, and Co-IP in cancer cells

    PMID:38378967

    Open questions at the time
    • Single lab in cancer context
    • Generality beyond RAD21/PI3K loci unknown
  20. 2024 Medium

    Placed NIPBL in a shared NHEJ-promoting pathway with BRD2 at immunoglobulin switch regions.

    Evidence Co-IP, CSR junction analysis, γH2AX foci, and ChIP at switch regions

    PMID:38567724

    Open questions at the time
    • Whether BRD2 stabilization of NIPBL is direct or chromatin-mediated unresolved
    • Single lab
  21. 2025 High

    Quantified full-length NIPBL as a tight DNA anchor in the loop extrusion mechanochemical cycle and defined an ATP-modulated STAG1-dependent DNA grabbing site.

    Evidence Mass photometry and in vitro binding with purified components and mutants

    PMID:40763028

    Open questions at the time
    • Coupling of anchor function to step-wise extrusion kinetics not fully resolved
    • In-cell relevance of measured affinities not established
  22. 2025 Medium

    Mapped NIPBL LxxLL motif clusters that separately maintain the MAU2 heterodimer and bind steroid receptor ligand-binding domains, predicting a GR-NIPBL-MAU2 ternary complex at enhancers.

    Evidence LxxLL mutagenesis, Co-IP, AlphaFold2 modeling, docking, and genome-wide binding

    PMID:40377219

    Open questions at the time
    • Ternary complex inferred computationally, not solved experimentally
    • Functional output of each motif cluster incompletely separated
  23. 2025 High

    Defined which genome contacts depend on NIPBL by showing acute depletion impairs long structural loops while most cis-regulatory element loops form normally after mitosis.

    Evidence NIPBL degron during mitotic exit with Hi-C, expression analysis, and modeling

    PMID:41974991

    Open questions at the time
    • Mechanism allowing CRE loops to persist without extrusion unclear
    • Single cell-type/timing window
  24. 2026 High

    Showed NIPBL preferentially supports cell-identity gene programs and super-enhancer proximity, while a STAG1-dependent loop subset persists after NIPBL loss.

    Evidence Acute NIPBL degron in multiple cell types with Hi-C, ChIP-seq, and RNA-seq

    PMID:41699137

    Open questions at the time
    • Mechanism of NIPBL-independent STAG1 loop maintenance unresolved
    • Determinants of cell-identity gene selectivity not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how NIPBL's loop-extrusion activity, its cohesin-independent promoter/HDAC and DNA-repair functions, and its RNA-processing roles are mechanistically integrated to produce the locus-specific transcriptional dysregulation underlying Cornelia de Lange syndrome.
  • No unified model linking extrusion defects to specific dysregulated CdLS genes
  • Relative contribution of cohesin-dependent versus cohesin-independent NIPBL functions to disease unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-73894 DNA Repair 3 R-HSA-1640170 Cell Cycle 2
Partners
BRD2BRD4HDAC1HDAC3HP1ΓMAU2STAG1ZFP609
Complex memberships
NIPBL/MAU2 cohesin loadercohesin

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Cryo-EM structure of human cohesin bound to its loader NIPBL and DNA revealed that cohesin and NIPBL interact extensively and together form a central tunnel to entrap a 72-base pair DNA. NIPBL and DNA promote engagement of cohesin's ATPase head domains and ATP binding. The hinge domains of cohesin adopt an 'open washer' conformation and dock onto the STAG1 subunit, explaining synergistic activation of cohesin by NIPBL and DNA. Cryo-electron microscopy (cryo-EM) structural determination Science High 32409525
2017 NIPBL/Scc2 binds dynamically to chromatin principally through association with cohesin, displaying 'stop-and-go' or 'hopping' motion between chromosomal cohesin rings after loading. Low stoichiometry relative to cohesin and high affinity for chromosomal cohesin enables rapid movement from one cohesin complex to another, suggesting a post-loading function distinct from initial cohesin loading. Fluorescence recovery after photobleaching (FRAP) and single-molecule tracking in human cells eLife High 28914604
2023 High-speed AFM imaging revealed that cohesin-NIPBL captures DNA through arm extension assisted by 'feet' (shorter protrusions), followed by transfer of DNA to the lower compartment (SMC heads, RAD21, SA1, and NIPBL). Arm extension leads to capture of a second DNA segment and initiation of a DNA loop independently of ATP hydrolysis. The feet are likely contributed by C-terminal domains of SA1 and NIPBL and transiently bind DNA to facilitate cohesin loading. Distinct forward and reverse DNA loop extrusion steps were directly visualized. High-speed atomic force microscopy (HS-AFM) imaging Journal of Biological Chemistry High 37774974
2025 Mass photometry quantification established that full-length NIPBL tightly binds DNA, acting as a DNA anchor during the mechanochemical loop extrusion cycle. STAG1 binds tightly to the trimeric SMC1/SMC3/SCC1 complex and together they weakly but cooperatively bind DNA. An ATP-modulated DNA binding site created by STAG1 interaction with SMC1/SMC3/SCC1 is important for repeated grabbing and release of DNA critical to loop extrusion. Cohesin mutants incapable of head engagement showed negligible differences in overall DNA affinity. Mass photometry, in vitro binding assays with purified components and mutants Proceedings of the National Academy of Sciences High 40763028
2022 Several CdLS-associated NIPBL missense mutations impair the DNA loop extrusion activity of the cohesin complex in vitro, suggesting that defects in cohesin-mediated loop extrusion—required for chromatin loop and TAD formation—contribute to the etiology of CdLS by altering enhancer-gene interactions. In vitro DNA loop extrusion assay with CdLS mutant NIPBL proteins Proceedings of the National Academy of Sciences High 35476527
2020 A MAU2 variant causing CdLS (7 amino acid deletion) impairs the interaction between MAU2 and the NIPBL N-terminus. However, an alternative translation initiation from an NIPBL early truncating mutation produces a form of NIPBL lacking the N-terminal MAU2-binding region that cannot interact with MAU2 but still binds DNA and mediates cohesin loading, demonstrating that cohesin loading can occur independently of a functional NIPBL/MAU2 heterodimer. Engineered cell lines with NIPBL truncating mutations, co-immunoprecipitation, alternative translation analysis Cell Reports High 32433956
2008 NIPBL directly interacts with histone deacetylases HDAC1 and HDAC3 via a conserved 163-amino-acid region in NIPBL that is mutated in CdLS patients. This interaction recruits HDACs to mediate local chromatin modifications and represses promoter activity, an effect abolished by CdLS missense mutations in this region or by chemical HDAC inhibition. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, reporter gene assay with GAL4-DBD fusion Nucleic Acids Research High 18854353
2018 BRD4 interacts with NIPBL; a CdLS-like de novo BRD4 missense variant retained the ability to co-immunoprecipitate NIPBL but bound poorly to acetylated histones. BRD4 and NIPBL display correlated binding at super-enhancers and co-regulate developmental gene expression. Co-immunoprecipitation, ChIP-seq, patient variant functional analysis Nature Genetics High 29379197
2019 NIPBL directly interacts with BRD4 via the BRD4 ET domain (shown in yeast and in cells). NIPBL and BRD4 mutually stabilize each other at co-regulated promoters. Genetic interaction between Drosophila orthologs Nipped-B and fs(1)h confirmed functional cooperation. CdLS patient fibroblasts with NIPBL mutations show reduced BRD4 at co-occupied promoters. Yeast interaction assay, co-immunoprecipitation in human cells, ChIP-seq, RNA-seq, Drosophila genetic epistasis Cell Death & Disease High 31320616
2014 NIPBL binds chromatin with different timing than cohesin; high-affinity NIPBL binding sites localize predominantly to promoters of active genes rather than cohesin-bound regions. NIPBL knockdown reduces transcription of these genes differently from cohesin knockdown, demonstrating a cohesin-independent role for NIPBL in transcriptional regulation at active gene promoters. ChIP-seq, siRNA knockdown, gene expression analysis, timing assays in somatic cells PLoS Genetics High 24550742
2016 Nipbl interacts with the neural transcription factor Zfp609 and the Integrator complex (which functions in RNA polymerase II pause release) at gene promoters containing paused RNA Pol II. Depletion of Nipbl or Zfp609 from cortical neural progenitors in vivo impairs neuronal migration. Nipbl and Zfp609 co-occupy genomic binding sites independently of cohesin. Co-immunoprecipitation, ChIP-seq, in vivo cortical knockdown, proteomics (mass spectrometry for interaction partners) Neuron High 28041881
2017 NIPBL is recruited to DNA double-strand breaks (DSBs) via two independent mechanisms: (1) HP1γ recruits NIPBL to DSBs through an HP1-binding motif in the NIPBL N-terminus; (2) the C-terminal HEAT repeat domain independently targets NIPBL to laser microirradiation-induced damage. Both mechanisms are dependent on the RNF8/RNF168 ubiquitylation pathway, while the HEAT repeat domain additionally requires ATM or ATR kinase activity. Live-cell imaging of NIPBL recruitment to laser microirradiation sites, RNAi knockdown, domain deletion/mutation analysis Journal of Cell Science High 28167679
2011 Human NIPBL is recruited to DSB sites; recruitment requires MDC1, RNF168, and HP1γ. The C-terminal region containing HEAT repeats and an HP1-interacting motif mediates NIPBL's recruitment to DNA damage sites. Knockdown of MDC1, RNF168, or HP1γ each impaired NIPBL accumulation at damage foci. Immunofluorescence of NIPBL at microirradiation and I-PpoI-induced DSBs, RNAi knockdown of damage response factors Biochemical and Biophysical Research Communications Medium 21784059
2013 NIPBL deficiency in CdLS patient B lymphocytes causes a shift toward alternative microhomology-based end joining during immunoglobulin class switch recombination, with reduced early recruitment of 53BP1 to DSBs. This NIPBL role in NHEJ was confirmed in a plasmid-based end-joining assay and a yeast model, demonstrating an evolutionarily conserved function in NHEJ distinct from cohesion. Analysis of CSR junctions in patient B lymphocytes, plasmid-based end-joining assay, yeast model of NHEJ, 53BP1 recruitment by immunofluorescence Journal of Experimental Medicine High 24145515
2013 In Nipbl+/- mouse cells, bulk cohesin loading is unperturbed and sister chromatid cohesion is robust along chromosomes. DNA replication, DNA repair, and chromosome segregation are carried out efficiently. However, cohesin binding to specific promoters (e.g., Protocadherin genes in brain) is notably reduced, altering gene expression, supporting the model that CdLS developmental defects arise from transcriptional deregulation rather than cohesion failure. Cohesion assays, DNA replication and repair assays, chromosome segregation assays, ChIP for cohesin at specific loci, gene expression analysis in Nipbl+/- mouse cells Biochimica et Biophysica Acta High 23920377
2020 Calcium influx in activated neutrophils rapidly recruits NIPBL to thousands of active enhancers and promoters with distinct kinetics. At enhancers, NIPBL recruitment requires histone acetyltransferases P300/CBP (which maintain H3K27ac) and chromatin remodelers BRG1/BRM; at promoters, NIPBL occupancy is independent of BRG1/BRM and is associated with GC-rich DNA sequences. NIPBL-bound enhancers are enriched for NFAT, PU.1, and CEBP motifs. ChIP-seq, acute NIPBL degradation system, P300/CBP/BRG1/BRM depletion, calcium signaling manipulation Genes & Development High 33334824
2022 The glucocorticoid receptor (GR) interacts with NIPBL and the cohesin complex at the chromatin level, as demonstrated by mass spectrometry, genome mapping (ChIP-seq), and single-molecule tracking. This GR-NIPBL interaction promotes loop extrusion and long-range gene regulation. Loss of cohesin markedly diminishes TF concentration at specific nuclear confinement sites. Mass spectrometry, ChIP-seq, single-molecule tracking, cohesin depletion experiments Science Advances High 35353576
2025 Two clusters of LxxLL motifs in NIPBL regulate its dynamics, interactome, and transcriptional programs. One cluster interacts with MAU2 and is necessary for maintaining the NIPBL-MAU2 heterodimer. The second cluster binds specifically to the ligand-binding domains of steroid receptors (including GR). AlphaFold2 modeling and molecular docking revealed a GR-NIPBL-MAU2 ternary complex at enhancers. Multiple transcription factors interact with NIPBL-MAU2. LxxLL motif mutagenesis, co-immunoprecipitation, AlphaFold2 structural modeling, molecular docking, genome-wide binding studies Nucleic Acids Research Medium 40377219
2013 Nipbl/Mau2 heterodimer localizes to chromosomal axes from zygotene to mid-pachytene in germ cells of both sexes during mammalian meiotic prophase, consistent with a loading factor role for cohesin and condensin I (but not Smc5/6) during meiosis. Nipbl/Mau2 co-localizes next to Rad51 and γH2AX foci. Nipbl haploinsufficiency alters the distribution of γH2AX-marked DSBs during prophase I. Immunofluorescence/immunolocalization on spread spermatocyte and oocyte nuclei, genetic Nipbl+/- model Chromosoma Medium 23967866 24287868
2015 NIPBL mutations (but not SMC1A or SMC3 mutations) activate the RNA-sensing kinase PKR in human lymphoblastoid cells. NIPBL-deficient cells show reduced expression of RNA processing and modification genes, and non-coding RNAs from NIPBL mutant cells have less m6A modification and activate PKR in vitro. PKR inhibition partially reverses reduced proliferation, decreased protein synthesis, and increased apoptosis in NIPBL mutant cells. PKR activation assay, gene expression profiling, m6A methylation analysis, in vitro PKR activation by isolated RNAs, PKR inhibitor rescue Cell Reports Medium 26725122
2013 NIPBL disruption in CdLS patient cells causes visible chromatin decompaction, most pronounced across gene-rich regions. This decompaction is reproduced by siRNA-mediated NIPBL depletion in normal cells but is not observed following knockdown of cohesin component SMC3 or CTCF, demonstrating that NIPBL has a function in modulating chromatin architecture independent of SMC3/cohesin and CTCF. Fluorescence in situ hybridization (FISH) in CdLS patient cells and siRNA-depleted normal cells Human Molecular Genetics Medium 23760082
2009 Cohesin ChIP-seq in CdLS mutant human cells shows binding preference for intergenic regions, suggesting a cis-regulatory/boundary-insulator function. Cohesin binding is enriched within promoter regions of dysregulated genes and is significantly decreased in CdLS probands with NIPBL mutations, indicating cohesin acts as a transcription regulator at these sites. Genome-wide transcription profiling of 16 mutant CdLS cell lines, cohesin ChIP-seq PLoS Biology Medium 19468298
2022 Co-depletion of NIPBL and WAPL in human HCT116 cells restores the majority of gene misexpression caused by either knockdown alone (~2,000 genes affected by each), demonstrating that NIPBL and WAPL act as opposing cohesin regulators whose balance controls gene expression. Co-depletion of NIPBL and CTCF similarly rescues NIPBL-sensitive gene misexpression. siRNA knockdown of NIPBL, WAPL, and CTCF singly and in combination; RNA-seq gene expression analysis PLoS Genetics Medium 36449519
2022 Decreasing Wapl dosage in Nipbl heterozygous mice partially corrects gene expression dysregulation and embryonic growth defects, consistent with NIPBL and WAPL having opposing effects on cohesin DNA association that together regulate gene expression. Patterns of gene dysregulation in Wapl and Nipbl heterozygotes are highly similar. Mouse genetic epistasis (Nipbl+/-;Wapl+/- double heterozygotes), transcriptome profiling of embryonic brain Science Advances Medium 36449618
2024 NIPBL promotes RAD21 gene transcription by enhancing histone H3K27 demethylation via recruiting the lysine demethylase KDM6B to the RAD21 promoter, as shown by ChIP. NIPBL also disrupts the association between EZH2 and RAD21 to counteract EZH2-mediated repression of PI3K gene transcription. NIPBL transcript stability is increased by mRNA methylation. Chromatin immunoprecipitation (ChIP), methylated RNA immunoprecipitation (MeRIP), RNA decay assay, co-immunoprecipitation Communications Biology Medium 38378967
2024 BRD2 stabilizes NIPBL at immunoglobulin switch regions, and BRD2 or NIPBL loss produces comparable deregulation of switch-region synapsis, DNA damage response, and DNA repair pathway choice during class switch recombination, placing BRD2 and NIPBL in a shared NHEJ-promoting pathway. Co-immunoprecipitation of BRD2 and NIPBL, CSR junction analysis, γH2AX foci, ChIP at switch regions Nucleic Acids Research Medium 38567724
2014 Neural crest cell-specific inactivation of Nipbl in mice strongly affects craniofacial development. Mau2 single homozygous mutants exhibited a more severe craniofacial phenotype than Nipbl;Mau2 double homozygous mutants, suggesting that Mau2/Nipbl interaction is required not only for cohesin loading but may also restrict the level of Nipbl involved in gene expression regulation. Conditional gene knockout in neural crest cells (Cre-lox), comparison of single and double homozygous mutant phenotypes Genesis Medium 24700590
2025 Acute NIPBL depletion during mitosis-to-G1 transition impaired structural loop formation proportionally to loop length, but most cis-regulatory element (CRE) loops, regardless of length, were established normally, demonstrating that postmitotic establishment of regulatory contacts and gene transcription can occur largely independently of NIPBL-driven chromatin loop extrusion. Acute NIPBL degradation (degron system) during mitotic exit, Hi-C/chromatin conformation capture, gene expression analysis, computational modeling Nature Genetics High 41974991
2026 Acute NIPBL depletion in multiple cell types revealed that many chromatin loops rapidly diminish upon NIPBL loss but a subset of cohesin-dependent loops requiring STAG1 (not STAG2) persist for hours after NIPBL removal. NIPBL specifically regulates cell identity genes by supporting local genome conformation with greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation. Acute NIPBL degradation (degron) in multiple cell types, Hi-C, ChIP-seq, RNA-seq, mitotic exit experiments Nature Genetics High 41699137
2025 Nipbl regulates CRL4 E3 ubiquitin ligase activity by controlling transcription of ddb1 (a CRL4 component) in zebrafish embryos. Developmental abnormalities from Nipbl knockdown are partially rescued by exogenous ddb1 mRNA, placing Nipbl upstream of CRL4. Aberrant accumulation of CRL4 substrate pparαa is sufficient to produce developmental defects. Morpholino knockdown in zebrafish, mRNA rescue experiments, LC-MS proteomics for CRL4 substrates, overexpression assays Developmental Dynamics Medium 40396618
2025 NIPBL-mediated cohesin function is required for proper de novo activation of lineage-specifying genes during mouse pluripotency transitions and germ-layer specification. Mechanistically, NIPBL physically brings distal enhancers and target promoters into proximity to translate epigenetic priming into transcriptional output. NIPBL also prevents ectopic gene de-repression (safeguards transcriptional fidelity) during cell state transitions. Acute NIPBL degron system, single-gene imaging, single-cell multi-omics, bulk multi-omics during pluripotency transitions and germ-layer specification bioRxiv (preprint)preprint Medium 41509465

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nature genetics 554 15146186
2004 NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nature genetics 492 15146185
2004 NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. American journal of human genetics 240 15318302
2009 Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome. PLoS genetics 202 19763162
2009 Transcriptional dysregulation in NIPBL and cohesin mutant human cells. PLoS biology 199 19468298
2020 Cryo-EM structure of the human cohesin-NIPBL-DNA complex. Science (New York, N.Y.) 164 32409525
2018 BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome. Nature genetics 112 29379197
2014 A cohesin-independent role for NIPBL at promoters provides insights in CdLS. PLoS genetics 111 24550742
2007 Clinical score of 62 Italian patients with Cornelia de Lange syndrome and correlations with the presence and type of NIPBL mutation. Clinical genetics 88 17661813
2017 Scc2/Nipbl hops between chromosomal cohesin rings after loading. eLife 85 28914604
2011 Multifactorial origins of heart and gut defects in nipbl-deficient zebrafish, a model of Cornelia de Lange Syndrome. PLoS biology 84 22039349
2010 Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome. American journal of medical genetics. Part A 71 20358602
2020 Calcium signaling instructs NIPBL recruitment at active enhancers and promoters via distinct mechanisms to reconstruct genome compartmentalization. Genes & development 60 33334824
2016 Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration. Neuron 54 28041881
2008 The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications. Nucleic acids research 50 18854353
2006 Father-to-daughter transmission of Cornelia de Lange syndrome caused by a mutation in the 5' untranslated region of the NIPBL Gene. Human mutation 50 16799922
2020 MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome. Cell reports 49 32433956
2017 Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage. Journal of cell science 44 28167679
2013 Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts. Cell death & disease 44 24136230
2023 NIPBL and cohesin: new take on a classic tale. Trends in cell biology 42 37062615
2022 The glucocorticoid receptor associates with the cohesin loader NIPBL to promote long-range gene regulation. Science advances 42 35353576
2019 The Cornelia de Lange Syndrome-associated factor NIPBL interacts with BRD4 ET domain for transcription control of a common set of genes. Cell death & disease 42 31320616
2013 Reduction of Nipbl impairs cohesin loading locally and affects transcription but not cohesion-dependent functions in a mouse model of Cornelia de Lange Syndrome. Biochimica et biophysica acta 38 23920377
2011 Recruitment of the cohesin loading factor NIPBL to DNA double-strand breaks depends on MDC1, RNF168 and HP1γ in human cells. Biochemical and biophysical research communications 37 21784059
2021 A Novel NIPBL-NACC1 Gene Fusion Is Characteristic of the Cholangioblastic Variant of Intrahepatic Cholangiocarcinoma. The American journal of surgical pathology 34 33999553
2013 A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination. The Journal of experimental medicine 33 24145515
2012 NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype-phenotype correlation. Genetics in medicine : official journal of the American College of Medical Genetics 32 22241092
2013 Regional chromatin decompaction in Cornelia de Lange syndrome associated with NIPBL disruption can be uncoupled from cohesin and CTCF. Human molecular genetics 31 23760082
2018 NIPBL+/- haploinsufficiency reveals a constellation of transcriptome disruptions in the pluripotent and cardiac states. Scientific reports 28 29348408
2016 Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects. PLoS biology 26 27606604
2015 NIPBL Controls RNA Biogenesis to Prevent Activation of the Stress Kinase PKR. Cell reports 26 26725122
2020 Whole-genome sequencing reveals complex chromosome rearrangement disrupting NIPBL in infant with Cornelia de Lange syndrome. American journal of medical genetics. Part A 24 32125084
2018 Roles of NIPBL in maintenance of genome stability. Seminars in cell & developmental biology 23 30096364
2014 Neural crest cell-specific inactivation of Nipbl or Mau2 during mouse development results in a late onset of craniofacial defects. Genesis (New York, N.Y. : 2000) 23 24700590
2006 Paternal gonadal mosaicism of NIPBL mutation in a father of siblings with Cornelia de Lange syndrome. Prenatal diagnosis 23 16958143
2022 Cornelia de Lange syndrome mutations in NIPBL can impair cohesin-mediated DNA loop extrusion. Proceedings of the National Academy of Sciences of the United States of America 22 35476527
2012 Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients. European journal of human genetics : EJHG 22 22353942
2019 NIPBL: a new player in myeloid cell differentiation. Haematologica 21 30630974
2016 A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome. Clinical genetics 21 26701315
2013 Molecular characterization of a mosaic NIPBL deletion in a Cornelia de Lange patient with severe phenotype. European journal of medical genetics 21 23313159
2013 Cohesin loading factor Nipbl localizes to chromosome axes during mammalian meiotic prophase. Cell division 21 23967866
2013 Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I. Chromosoma 21 24287868
2022 Co-depletion of NIPBL and WAPL balance cohesin activity to correct gene misexpression. PLoS genetics 20 36449519
2014 Functional characterization of NIPBL physiological splice variants and eight splicing mutations in patients with Cornelia de Lange syndrome. International journal of molecular sciences 19 24918291
2010 Development of NIPBL locus-specific database using LOVD: from novel mutations to further genotype-phenotype correlations in Cornelia de Lange Syndrome. Human mutation 19 20824775
2017 Downregulation of Cohesin Loading Factor Nipped-B-Like Protein (NIPBL) Induces Cell Cycle Arrest, Apoptosis, and Autophagy of Breast Cancer Cell Lines. Medical science monitor : international medical journal of experimental and clinical research 18 28987049
2010 Cornelia de Lange syndrome case due to genomic rearrangements including NIPBL. European journal of medical genetics 18 20727427
2022 uORF-introducing variants in the 5'UTR of the NIPBL gene as a cause of Cornelia de Lange syndrome. Human mutation 15 35446447
2018 Inhibition of NIPBL enhances the chemosensitivity of non-small-cell lung cancer cells via the DNA damage response and autophagy pathway. OncoTargets and therapy 14 29670369
2007 Prenatal/neonatal pathology in two cases of Cornelia de Lange syndrome harboring novel mutations of NIPBL. Genetics in medicine : official journal of the American College of Medical Genetics 14 17413424
2022 Decreasing Wapl dosage partially corrects embryonic growth and brain transcriptome phenotypes in Nipbl embryos. Science advances 13 36449618
2016 Identification and Functional Characterization of Two Intronic NIPBL Mutations in Two Patients with Cornelia de Lange Syndrome. BioMed research international 13 26925417
2012 Cornelia de Lange syndrome with NIPBL mutation and mosaic Turner syndrome in the same individual. BMC medical genetics 13 22676896
2017 Regulation of the cohesin-loading factor NIPBL: Role of the lncRNA NIPBL-AS1 and identification of a distal enhancer element. PLoS genetics 12 29261648
2010 Brachmann-de Lange syndrome with congenital diaphragmatic hernia and NIPBL gene mutation. Congenital anomalies 12 20156239
2021 MicroRNA-99b inhibits NSCLC cell invasion and migration by directly targeting NIPBL. European review for medical and pharmacological sciences 11 33660799
2020 Dysregulation of NIPBL leads to impaired RUNX1 expression and haematopoietic defects. Journal of cellular and molecular medicine 11 32323916
2013 Copy number analysis of NIPBL in a cohort of 510 patients reveals rare copy number variants and a mosaic deletion. Molecular genetics & genomic medicine 11 24689074
2012 Spectrum of NIPBL gene mutations in Polish patients with Cornelia de Lange syndrome. Journal of applied genetics 11 23254390
2008 Search for genomic imbalances in a cohort of 24 Cornelia de Lange patients negative for mutations in the NIPBL and SMC1L1 genes. Clinical genetics 11 18798846
2023 Case report: Novel NIPBL-BEND2 fusion gene identified in osteoblastoma-like phosphaturic mesenchymal tumor of the fibula. Frontiers in oncology 9 36686800
2024 Elevated microRNA-187 causes cardiac endothelial dysplasia to promote congenital heart disease through inhibition of NIPBL. The Journal of clinical investigation 8 39585787
2023 High-speed AFM imaging reveals DNA capture and loop extrusion dynamics by cohesin-NIPBL. The Journal of biological chemistry 8 37774974
2019 Clinical Diagnosis of Classical Cornelia de Lange Syndrome Made From Postmortem Examination of Second Trimester Fetus With Novel NIPBL Pathogenic Variant. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 8 30890023
2018 Mosaic Intronic NIPBL Variant in a Family With Cornelia de Lange Syndrome. Frontiers in genetics 8 30057591
2019 Next generation sequencing identified two novel mutations in NIPBL and a frame shift mutation in CREBBP in three Chinese children. Orphanet journal of rare diseases 7 30770747
2014 Severe ipsilateral musculoskeletal involvement in a Cornelia de Lange patient with a novel NIPBL mutation. European journal of medical genetics 7 24874887
2011 Cornelia de Lange syndrome: antenatal diagnosis in two consecutive pregnancies due to rare gonadal mosaicism of NIPBL gene mutation. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 7 21338332
2024 NIPBL-mediated RAD21 facilitates tumorigenicity by the PI3K pathway in non-small-cell lung cancer. Communications biology 6 38378967
2014 Two novel NIPBL gene mutations in Chinese patients with Cornelia de Lange syndrome. Gene 6 25447906
2010 Cornelia de Lange Syndrome with NIPBL gene mutation: a case report. Journal of Korean medical science 6 21165303
2025 Transcription factors form a ternary complex with NIPBL/MAU2 to localize cohesin at enhancers. Nucleic acids research 5 40377219
2024 Malignant Bone-Forming Neoplasm With NIPBL::BEND2 Fusion. Genes, chromosomes & cancer 5 39604143
2022 Deep intronic NIPBL de novo mutations and differential diagnoses revealed by whole genome and RNA sequencing in Cornelia de Lange syndrome patients. Human mutation 5 35842780
2019 Establishment of resveratrol and its derivatives as neuroprotectant against monocrotophos-induced alteration in NIPBL and POU4F1 protein through molecular docking studies. Environmental science and pollution research international 5 31786755
2015 Cornelia de Lange syndrome due to mosaic NIPBL mutation: antenatal presentation with sacrococcygeal teratoma. BMJ case reports 5 26276849
2012 An atypical facial appearance and growth pattern in a child with Cornelia de Lange Syndrome: an intragenic deletion predicting loss of the N-terminal region of NIPBL. Clinical dysmorphology 5 21934607
2012 Cornelia de Lange Syndrome: A Newborn with Imperforate Anus and a NIPBL Mutation. Case reports in genetics 5 23304577
2025 Cholangioblastic Cholangiocarcinoma ( NIPBL :: NACC1 Cholangiocarcinoma) : Expanded Morphologic Spectrum and Further Genetic Characterization. The American journal of surgical pathology 4 39815455
2019 Molecular characterization of two novel intronic variants of NIPBL gene detected in unrelated Cornelia de Lange syndrome patients. BMC medical genetics 4 30606125
2018 Recurrence and Familial Inheritance of Intronic NIPBL Pathogenic Variant Associated With Mild CdLS. Frontiers in neurology 4 30538663
2026 Acute NIPBL depletion reveals in vivo dynamics of loop extrusion and its role in transcription activation. Nature genetics 3 41699137
2025 Identification of De Novo Chromosomal Translocations Disrupting NIPBL in a Patient With Cornelia de Lange Syndrome by Full Genome Analysis. Molecular genetics & genomic medicine 3 40525380
2025 NIPBL and STAG1 enable loop extrusion by providing differential DNA-cohesin affinity. Proceedings of the National Academy of Sciences of the United States of America 3 40763028
2024 BRD2 promotes antibody class switch recombination by facilitating DNA repair in collaboration with NIPBL. Nucleic acids research 3 38567724
2022 A Novel de Novo Variant in 5' UTR of the NIPBL Associated with Cornelia de Lange Syndrome. Genes 3 35627125
2022 In Silico Analysis of Seven PCR Markers Developed from the CHD1, NIPBL and SPIN Genes Followed by Laboratory Testing Shows How to Reliably Determine the Sex of Musophagiformes Species. Genes 3 35627317
2021 Case Report: Prenatal Whole-Exome Sequencing to Identify a Novel Heterozygous Synonymous Variant in NIPBL in a Fetus With Cornelia de Lange Syndrome. Frontiers in genetics 3 33633789
2011 Identification of a novel de novo mutation in the NIPBL gene in an Iranian patient with Cornelia de Lange syndrome: A case report. Journal of medical case reports 3 21707975
2026 De novo formation of cis-regulatory contacts in the absence of NIPBL-driven chromatin loop extrusion. Nature genetics 2 41974991
2025 Transcription factors form a ternary complex with NIPBL/MAU2 to localize cohesin at enhancers. bioRxiv : the preprint server for biology 2 39713324
2024 The NIPBL-gene mutation of a Cornelia de Lange Syndrome patient causes deficits in the hepatocyte differentiation of induced Pluripotent Stem Cells via altered chromatin-accessibility. Cellular and molecular life sciences : CMLS 2 39453535
2023 Nipbl Haploinsufficiency Leads to Delayed Outflow Tract Septation and Aortic Valve Thickening. International journal of molecular sciences 2 37958548
2021 Case Report: Novel NIPBL Variants Cause Cornelia de Lange Syndrome in Chinese Patients. Frontiers in genetics 2 34394191
2020 De novo NIPBL Mutations in Vietnamese Patients with Cornelia de Lange Syndrome. Medicina (Kaunas, Lithuania) 2 32074972
2020 A Novel Mutation in NIPBL Gene with the Cornelia de Lange Syndrome and a 10q11.22-q11.23 Microdeletion in the Same Individual. Journal of pediatric genetics 2 35990037
2018 A Novel Frameshift Mutation (c.5387_5388insTT) in NIPBL in Cornelia de Lange Syndrome with Severe Phenotype. Annals of clinical and laboratory science 2 29531005
2010 Clinical and genetic analysis of Korean patients with Cornelia de Lange syndrome: two novel NIPBL mutations. Annals of clinical and laboratory science 2 20124326
2025 Protein turnover downstream of the Nipbl/CRL4 axis contributes to abnormal development in zebrafish embryos. Developmental dynamics : an official publication of the American Association of Anatomists 1 40396618
2025 NIPBL-mediated 3D genome folding translates enhancer priming into gene activation and safeguards lineage fidelity during embryonic transitions. bioRxiv : the preprint server for biology 1 41509465

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