Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation

Oana Paun; Yu Xuan Tan; Harshil Patel; Stephanie Strohbuecker; Avinash Ghanate; Clementina Cobolli-Gigli; Miriam Llorian Sopena; Lina Gerontogianni; Robert Goldstone; Siew Lan Ang; Francois Guillemot; Cristina Dias

doi:10.1101/gad.350269.122

Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation

Oana Paun, Yu Xuan Tan, Harshil Patel, Stephanie Strohbuecker, Avinash Ghanate, Clementina Cobolli-Gigli, Miriam Llorian Sopena, Lina Gerontogianni, Robert Goldstone, Siew Lan Ang, Francois Guillemot, Cristina Dias^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.

Original language	English
Pages (from-to)	218-242
Number of pages	25
Journal	Genes and Development
Volume	37
Issue number	5-6
Early online date	17 Mar 2023
DOIs	https://doi.org/10.1101/gad.350269.122
Publication status	Published - 2023

Keywords

mSWI/SNF
neurogenesis
pioneer transcription factor
chromatin regulation
ASCL1
ChIP-seq
ATAC-seq
scRNA-seq
neural stem cell

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Paun, O., Tan, Y. X., Patel, H., Strohbuecker, S., Ghanate, A., Cobolli-Gigli, C., Llorian Sopena, M., Gerontogianni, L., Goldstone, R., Ang, S. L., Guillemot, F., & Dias, C. (2023). Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation. Genes and Development, 37(5-6), 218-242. https://doi.org/10.1101/gad.350269.122

@article{f4d0c7cb43bb43239eed7f60621c646b,

title = "Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation",

abstract = "Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.",

keywords = "mSWI/SNF, neurogenesis, pioneer transcription factor, chromatin regulation, ASCL1, ChIP-seq, ATAC-seq, scRNA-seq, neural stem cell",

author = "Oana Paun and Tan, {Yu Xuan} and Harshil Patel and Stephanie Strohbuecker and Avinash Ghanate and Clementina Cobolli-Gigli and {Llorian Sopena}, Miriam and Lina Gerontogianni and Robert Goldstone and Ang, {Siew Lan} and Francois Guillemot and Cristina Dias",

note = "Funding Information: We gratefully acknowledge the Human Embryo Stem Cell Unit, Advanced Sequencing Facility, Flow Cytometry Facility, Advanced Light Microscopy Facility, and Proteomics Facility at the Francis Crick Institute. We thank Adrienne Sullivan from the Quantitative Cell Biology Laboratory and Dinis Calado from the Immunity and Cancer Laboratory for experimental advice and feedback, and members of the Neural Stem Cell Biology Laboratory for feedback on the manuscript. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2033), the UK Medical Research Council (MRC; CC2033), and the Wellcome Trust (CC2033). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. This work was also supported by the Wellcome Trust (Career Development Fellowship 209568/Z/17/Z to C.D., and Investigator Award 106187/Z/14/Z to F.G.). The authors acknowledge providers of human fetal material: the joint MRC/Wellcome Trust (grant MR/R006237/1) Human Developmental Biology Resource (HDBR; https://www.hdbr.org). Human tissue used in this study was covered by material transfer agreements between the Francis Crick Institute and HDBR. Publisher Copyright: {\textcopyright} 2023 P{\u a}un et al.",

year = "2023",

doi = "10.1101/gad.350269.122",

language = "English",

volume = "37",

pages = "218--242",

journal = "Genes and Development",

issn = "0890-9369",

publisher = "Cold Spring Harbor Laboratory Press",

number = "5-6",

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Paun, O , Tan, YX, Patel, H, Strohbuecker, S, Ghanate, A, Cobolli-Gigli, C, Llorian Sopena, M, Gerontogianni, L, Goldstone, R, Ang, SL, Guillemot, F & Dias, C 2023, 'Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation', Genes and Development, vol. 37, no. 5-6, pp. 218-242. https://doi.org/10.1101/gad.350269.122

TY - JOUR

T1 - Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation

AU - Paun, Oana

AU - Tan, Yu Xuan

AU - Patel, Harshil

AU - Strohbuecker, Stephanie

AU - Ghanate, Avinash

AU - Cobolli-Gigli, Clementina

AU - Llorian Sopena, Miriam

AU - Gerontogianni, Lina

AU - Goldstone, Robert

AU - Ang, Siew Lan

AU - Guillemot, Francois

AU - Dias, Cristina

N1 - Funding Information: We gratefully acknowledge the Human Embryo Stem Cell Unit, Advanced Sequencing Facility, Flow Cytometry Facility, Advanced Light Microscopy Facility, and Proteomics Facility at the Francis Crick Institute. We thank Adrienne Sullivan from the Quantitative Cell Biology Laboratory and Dinis Calado from the Immunity and Cancer Laboratory for experimental advice and feedback, and members of the Neural Stem Cell Biology Laboratory for feedback on the manuscript. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2033), the UK Medical Research Council (MRC; CC2033), and the Wellcome Trust (CC2033). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. This work was also supported by the Wellcome Trust (Career Development Fellowship 209568/Z/17/Z to C.D., and Investigator Award 106187/Z/14/Z to F.G.). The authors acknowledge providers of human fetal material: the joint MRC/Wellcome Trust (grant MR/R006237/1) Human Developmental Biology Resource (HDBR; https://www.hdbr.org). Human tissue used in this study was covered by material transfer agreements between the Francis Crick Institute and HDBR. Publisher Copyright: © 2023 Păun et al.

PY - 2023

Y1 - 2023

N2 - Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.

AB - Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.

KW - mSWI/SNF

KW - neurogenesis

KW - pioneer transcription factor

KW - chromatin regulation

KW - ASCL1

KW - ChIP-seq

KW - ATAC-seq

KW - scRNA-seq

KW - neural stem cell

UR - http://www.scopus.com/inward/record.url?scp=85151575377&partnerID=8YFLogxK

U2 - 10.1101/gad.350269.122

DO - 10.1101/gad.350269.122

M3 - Article

SN - 0890-9369

VL - 37

SP - 218

EP - 242

JO - Genes and Development

JF - Genes and Development

IS - 5-6

ER -

Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation

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Keywords

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