Recurrent FOXA1 mutation redirects NIPBL chromatin distribution
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE315393 | GEO | 2026/05/06
REPOSITORIES: GEO
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Project description:Cohesin complex shapes 3D genome organization by extruding DNA loops, yet the mechanisms underlying its chromatin entry remain poorly understood. Here, we reveal that the cohesin loader NIPBL exhibits highly tissue-specific chromatin binding, in stark contrast to the conserved binding profiles of CTCF and RAD21. We identify pioneer transcription factors (TFs), notably FOXA1, as key mediators of NIPBL recruitment to chromatin. FOXA1 directs NIPBL to intra-TAD regions, enabling symmetric loop extrusion, while factors like ETS1 target NIPBL to TAD boundaries, supporting one-sided extrusion. Rapid depletion of FOXA1 disrupts NIPBL binding and intra-TAD loops, whereas loss of NIPBL impairs both intra-TAD and inter-TAD interactions, highlighting their roles in 3D genome folding. Strikingly, a recurrent FOXA1 mutation (R219S) in prostate cancer redirects NIPBL to TAD boundaries by recognizing a non-canonical motif, fostering a more insulated and tumor-aggressive genome. Evolutionary analysis points to a potential conserved role for TF-NIPBL cooperation in cohesin chromatin entry across species with tissue-specific adaptations. Our findings reveal that pioneer factors orchestrate cohesin loading to shape tissue-specific chromatin accessibility and 3D genome dynamics, a mechanism hijacked in diseases like cancer to rewire gene expression.
2026-05-07 | GSE293071 | GEO
Project description:Cohesin complex shapes 3D genome organization by extruding DNA loops, yet the mechanisms underlying its chromatin entry remain poorly understood. Here, we reveal that the cohesin loader NIPBL exhibits highly tissue-specific chromatin binding, in stark contrast to the conserved binding profiles of CTCF and RAD21. We identify pioneer transcription factors (TFs), notably FOXA1, as key mediators of NIPBL recruitment to chromatin. FOXA1 directs NIPBL to intra-TAD regions, enabling symmetric loop extrusion, while factors like ETS1 target NIPBL to TAD boundaries, supporting one-sided extrusion. Rapid depletion of FOXA1 disrupts NIPBL binding and intra-TAD loops, whereas loss of NIPBL impairs both intra-TAD and inter-TAD interactions, highlighting their roles in 3D genome folding. Strikingly, a recurrent FOXA1 mutation (R219S) in prostate cancer redirects NIPBL to TAD boundaries by recognizing a non-canonical motif, fostering a more insulated and tumor-aggressive genome. Evolutionary analysis points to a potential conserved role for TF-NIPBL cooperation in cohesin chromatin entry across species with tissue-specific adaptations. Our findings reveal that pioneer factors orchestrate cohesin loading to shape tissue-specific chromatin accessibility and 3D genome dynamics, a mechanism hijacked in diseases like cancer to rewire gene expression.
2026-05-07 | GSE293070 | GEO
Project description:Cohesin complex shapes 3D genome organization by extruding DNA loops, yet the mechanisms underlying its chromatin entry remain poorly understood. Here, we reveal that the cohesin loader NIPBL exhibits highly tissue-specific chromatin binding, in stark contrast to the conserved binding profiles of CTCF and RAD21. We identify pioneer transcription factors (TFs), notably FOXA1, as key mediators of NIPBL recruitment to chromatin. FOXA1 directs NIPBL to intra-TAD regions, enabling symmetric loop extrusion, while factors like ETS1 target NIPBL to TAD boundaries, supporting one-sided extrusion. Rapid depletion of FOXA1 disrupts NIPBL binding and intra-TAD loops, whereas loss of NIPBL impairs both intra-TAD and inter-TAD interactions, highlighting their roles in 3D genome folding. Strikingly, a recurrent FOXA1 mutation (R219S) in prostate cancer redirects NIPBL to TAD boundaries by recognizing a non-canonical motif, fostering a more insulated and tumor-aggressive genome. Evolutionary analysis points to a potential conserved role for TF-NIPBL cooperation in cohesin chromatin entry across species with tissue-specific adaptations. Our findings reveal that pioneer factors orchestrate cohesin loading to shape tissue-specific chromatin accessibility and 3D genome dynamics, a mechanism hijacked in diseases like cancer to rewire gene expression.
2026-05-07 | GSE293172 | GEO
Project description:Cohesin complex shapes 3D genome organization by extruding DNA loops, yet the mechanisms underlying its chromatin entry remain poorly understood. Here, we reveal that the cohesin loader NIPBL exhibits highly tissue-specific chromatin binding, in stark contrast to the conserved binding profiles of CTCF and RAD21. We identify pioneer transcription factors (TFs), notably FOXA1, as key mediators of NIPBL recruitment to chromatin. FOXA1 directs NIPBL to intra-TAD regions, enabling symmetric loop extrusion, while factors like ETS1 target NIPBL to TAD boundaries, supporting one-sided extrusion. Rapid depletion of FOXA1 disrupts NIPBL binding and intra-TAD loops, whereas loss of NIPBL impairs both intra-TAD and inter-TAD interactions, highlighting their roles in 3D genome folding. Strikingly, a recurrent FOXA1 mutation (R219S) in prostate cancer redirects NIPBL to TAD boundaries by recognizing a non-canonical motif, fostering a more insulated and tumor-aggressive genome. Evolutionary analysis points to a potential conserved role for TF-NIPBL cooperation in cohesin chromatin entry across species with tissue-specific adaptations. Our findings reveal that pioneer factors orchestrate cohesin loading to shape tissue-specific chromatin accessibility and 3D genome dynamics, a mechanism hijacked in diseases like cancer to rewire gene expression.
2026-05-07 | GSE293073 | GEO
Project description:Cohesin complex shapes 3D genome organization by extruding DNA loops, yet the mechanisms underlying its chromatin entry remain poorly understood. Here, we reveal that the cohesin loader NIPBL exhibits highly tissue-specific chromatin binding, in stark contrast to the conserved binding profiles of CTCF and RAD21. We identify pioneer transcription factors (TFs), notably FOXA1, as key mediators of NIPBL recruitment to chromatin. FOXA1 directs NIPBL to intra-TAD regions, enabling symmetric loop extrusion, while factors like ETS1 target NIPBL to TAD boundaries, supporting one-sided extrusion. Rapid depletion of FOXA1 disrupts NIPBL binding and intra-TAD loops, whereas loss of NIPBL impairs both intra-TAD and inter-TAD interactions, highlighting their roles in 3D genome folding. Strikingly, a recurrent FOXA1 mutation (R219S) in prostate cancer redirects NIPBL to TAD boundaries by recognizing a non-canonical motif, fostering a more insulated and tumor-aggressive genome. Evolutionary analysis points to a potential conserved role for TF-NIPBL cooperation in cohesin chromatin entry across species with tissue-specific adaptations. Our findings reveal that pioneer factors orchestrate cohesin loading to shape tissue-specific chromatin accessibility and 3D genome dynamics, a mechanism hijacked in diseases like cancer to rewire gene expression.
2026-05-07 | GSE293072 | GEO
Project description:While the cohesin complex is a key player in genome architecture, how it localizes to specific chromatin sites is not well understood. Recently, we and others have proposed that direct interactions with transcription factors (TFs) lead to the localization of the cohesin-loader complex (NIPBL/MAU2) within enhancers. Here, we identify two clusters of protein-protein interaction (PPI) motifs within the NIPBL sequence that regulate NIPBL dynamics, interactome, and NIPBL-dependent transcriptional programs. These PPIMs directly interact with chromatin-associated proteins, including TFs and one of them is necessary for the maintenance of the NIPBL-MAU2 heterodimer. Finally, using the glucocorticoid receptor (GR) as a model, we investigate its interaction surfaces with NIPBL and MAU2 using AlphaFold2 and surface plasmon resonance to uncover a TF-NIPBL-MAU2 ternary complex and present its importance in GR-dependent gene regulation.
2025-04-17 | PXD058574 | Pride
Project description:The gene expression program is regulated by a cell-type specific chromosome architecture. The connection between enhancer and promoter regions is dependent on a protein complex containing Nipbl, Mediator and Cohesin. To gain insights into the chromosome architecture of human differentiated cells, we profiled NIPBL and SMC1 in lymphoblastoid cells (LCLs). DNA was enriched from hLCLs and chromatin immunoprecipitations (ChIPs) were analyzed by Solexa sequencing. ChIPs were performed using an antibody against NIPBL and SMC1. Whole cell extract is provided for background.
2012-06-01 | E-GEOD-38395 | biostudies-arrayexpress
Project description:Multiple genes are dysregulated in hindlimb buds of Nipbl-deficient embryos. In all, more than 1000 limb bud genes were found to be significantly altered in expression by microarray analysis of E10.5 mouse hindlimb buds. Small changes in expression (mostly decreases) were observed for genes involved in FGF, BMP, and SHH pathways, as well as numerous genes involved in the Wnt/planar cell polarity signaling pathway. Genes involved in the Mediator complex, Cohesin function, and Hox gene expression and functions were also dysregulated in Nipbl deficient limb buds. Microarray analysis using RNA extracted from E10.5 hindlimb limb buds harvested from stage-matched Nipbl+/- (n=12) and wildtype (n=12)
2014-08-30 | E-GEOD-60932 | biostudies-arrayexpress
Project description:For its association with chromatin, the cohesin complex depends on a heterodimer formed by NIPBL and MAU2. Variants in NIPBL are the main cause of CdLS and result in NIPBL haploinsufficiency. Using CRISPR, we generated cells homozygous for an out-of-frame duplication in NIPBL. Remarkably, alternative translation initiation rescued NIPBL expression in these cells and produced an N-terminally truncated NIPBL that lacks MAU2-interaction domain, causing a dramatic reduction of MAU2 protein levels while a lot of NIPBL functions remain intact.
2020-06-10 | GSE122299 | GEO
Project description:RNA-seq of total RNA from Nipbl+/+ and Nipbl+/- dissociated cortical neurons at Day In Vitro (DIV10)
2021-02-28 | GSE161796 | GEO