BAF complexes cooperate with lineage-restricted transcription factors to establish cell-state-specific regulatory programs
- 1Princess Maxima Center for Pediatric Oncology
Abstract
BRG1/BRM-associated factor (BAF) complexes are essential regulators of chromatin organization and cell identity. Genes encoding BAF subunits are among the most frequently mutated in human cancer. Yet, how disruption of a single subunit gives rise to distinct tumor states remains poorly understood. Atypical teratoid rhabdoid tumors (ATRTs) provide a compelling model, as they are uniformly driven by bi-allelic loss of the BAF subunit SMARCB1, yet segregate into distinct molecular subtypes. Using integrated multi-omics profiling of patient-derived ATRT organoids and primary tumor tissues, we show that transcriptional and chromatin accessibility changes upon SMARCB1 reconstitution are directed by subtype- and lineage-specific transcription factor (TF) repertoires. Genome-wide binding and transcriptomic analyses reveal that SMARCB1 reconstitution enables the lineage-specific TF RFX4 to engage regulatory elements and activate neuronal differentiation programs, partially reprogramming ATRT-MYC toward an ATRT-SHH-like identity. Together, these findings demonstrate that SMARCB1 loss disrupts TF-dependent chromatin priming, revealing that the lineage-specific regulatory output of BAF complexes is constrained by the underlying TF repertoire.
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BibTeX
@misc{he2026complexes,
title = {{BAF complexes cooperate with lineage-restricted transcription factors to establish cell-state-specific regulatory programs}},
author = {J. He and C. Rios Arceo and N. Anderson and W. Teunissen and I. Paassen and S. Jongsma and E. de Wit and M. Kool and N. Q. Liu and J. Drost},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.08.764927},
url = {https://www.biorxiv.org/content/10.64898/2026.11.08.764927v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - BAF complexes cooperate with lineage-restricted transcription factors to establish cell-state-specific regulatory programs
AU - J. He
AU - C. Rios Arceo
AU - N. Anderson
AU - W. Teunissen
AU - I. Paassen
AU - S. Jongsma
AU - E. de Wit
AU - M. Kool
AU - N. Q. Liu
AU - J. Drost
PY - 2026
DA - 2026/11/08
PB - bioRxiv
DO - 10.64898/2026.11.08.764927
UR - https://www.biorxiv.org/content/10.64898/2026.11.08.764927v1
AB - BRG1/BRM-associated factor (BAF) complexes are essential regulators of chromatin organization and cell identity. Genes encoding BAF subunits are among the most frequently mutated in human cancer. Yet, how disruption of a single subunit gives rise to distinct tumor states remains poorly understood. Atypical teratoid rhabdoid tumors (ATRTs) provide a compelling model, as they are uniformly driven by bi-allelic loss of the BAF subunit SMARCB1, yet segregate into distinct molecular subtypes. Using integrated multi-omics profiling of patient-derived ATRT organoids and primary tumor tissues, we show that transcriptional and chromatin accessibility changes upon SMARCB1 reconstitution are directed by subtype- and lineage-specific transcription factor (TF) repertoires. Genome-wide binding and transcriptomic analyses reveal that SMARCB1 reconstitution enables the lineage-specific TF RFX4 to engage regulatory elements and activate neuronal differentiation programs, partially reprogramming ATRT-MYC toward an ATRT-SHH-like identity. Together, these findings demonstrate that SMARCB1 loss disrupts TF-dependent chromatin priming, revealing that the lineage-specific regulatory output of BAF complexes is constrained by the underlying TF repertoire.
ER -