BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming

Kenan Sevinç; Gülben Gürhan Sevinç; Ayşe Derya Cavga; Martin Philpott; Simge Kelekçi; Hazal Can; Adam P. Cribbs; Abdullah Burak Yıldız; Alperen Yılmaz; Enes Sefa Ayar; Dilşad H. Arabacı; James E. Dunford; Deniz Ata; Logan H. Sigua; Jun Qi; Udo Oppermann; Tamer T. Onder

doi:10.1016/j.stemcr.2022.10.005

BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming

Kenan Sevinç, Gülben Gürhan Sevinç, Ayşe Derya Cavga, Martin Philpott, Simge Kelekçi, Hazal Can, Adam P. Cribbs, Abdullah Burak Yıldız, Alperen Yılmaz, Enes Sefa Ayar, Dilşad H. Arabacı, James E. Dunford, Deniz Ata, Logan H. Sigua, Jun Qi, Udo Oppermann, Tamer T. Onder^*

^*Corresponding author for this work

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

10 Citations (Scopus)

Abstract

Epigenetic reprogramming to pluripotency requires extensive remodeling of chromatin landscapes to silence existing cell-type-specific genes and activate pluripotency genes. ATP-dependent chromatin remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of recently identified Bromodomain-containing protein 9 (BRD9) and the associated non-canonical BRG1-associated factors (ncBAF) complex in reprogramming remains unknown. Here, we show that genetic or chemical inhibition of BRD9, as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, increase human somatic cell reprogramming efficiency and can replace KLF4 and c-MYC. We find that BRD9 is dispensable for human induced pluripotent stem cells under primed but not under naive conditions. Mechanistically, BRD9 inhibition downregulates fibroblast-related genes and decreases chromatin accessibility at somatic enhancers. BRD9 maintains the expression of transcriptional regulators MN1 and ZBTB38, both of which impede reprogramming. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers chromatin-based barriers to reprogramming.

Original language	English
Pages (from-to)	2629-2642
Number of pages	14
Journal	Stem Cell Reports
Volume	17
Issue number	12
DOIs	https://doi.org/10.1016/j.stemcr.2022.10.005
Publication status	Published - 13 Dec 2022
Externally published	Yes

Funding

We thank Ahmet Kocabay and Ali Cihan Taşkın for help with mouse experiments, and Arzu Ruacan (Koç University, School of Medicine, Department of Pathology) for examination of histological sections. The authors gratefully acknowledge use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM), funded by the Republic of Turkey Ministry of Development. K.S. and D.H.A. were supported by TUBITAK BIDEB Scholarship. Funding: Newton Advanced Fellowship (T.T.O.), TUBITAK Projects 231S182 and 219Z209 (T.T.O.), Arthritis Research UK, program grant 20522 (U.O.), Cancer Research UK (U.O.), LEAN project of the Leducq Foundation (U.O.), People Program Marie Curie Actions of the European Union's Seventh Framework Program FP7/2007–2013 under REA grant agreement no. 609305 (U.O.). The authors declare no competing interests. We thank Ahmet Kocabay and Ali Cihan Taşkın for help with mouse experiments, and Arzu Ruacan (Koç University, School of Medicine, Department of Pathology) for examination of histological sections. The authors gratefully acknowledge use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM), funded by the Republic of Turkey Ministry of Development . K.S. and D.H.A. were supported by TUBITAK BIDEB Scholarship. Funding: Newton Advanced Fellowship (T.T.O.), TUBITAK Projects 231S182 and 219Z209 (T.T.O.), Arthritis Research UK , program grant 20522 (U.O.), Cancer Research UK (U.O.), LEAN project of the Leducq Foundation (U.O.), People Program Marie Curie Actions of the European Union’s Seventh Framework Program FP7/2007–2013 under REA grant agreement no. 609305 (U.O.).

All Science Journal Classification (ASJC) codes

Biochemistry
Genetics
Developmental Biology
Cell Biology

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10.1016/j.stemcr.2022.10.005

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Sevinç, K., Sevinç, G. G., Cavga, A. D., Philpott, M., Kelekçi, S., Can, H., Cribbs, A. P., Yıldız, A. B., Yılmaz, A., Ayar, E. S., Arabacı, D. H., Dunford, J. E., Ata, D., Sigua, L. H., Qi, J., Oppermann, U., & Onder, T. T. (2022). BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming. Stem Cell Reports, 17(12), 2629-2642. https://doi.org/10.1016/j.stemcr.2022.10.005

@article{d52f79cb34154246b05d9c8f24a27e04,

title = "BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming",

abstract = "Epigenetic reprogramming to pluripotency requires extensive remodeling of chromatin landscapes to silence existing cell-type-specific genes and activate pluripotency genes. ATP-dependent chromatin remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of recently identified Bromodomain-containing protein 9 (BRD9) and the associated non-canonical BRG1-associated factors (ncBAF) complex in reprogramming remains unknown. Here, we show that genetic or chemical inhibition of BRD9, as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, increase human somatic cell reprogramming efficiency and can replace KLF4 and c-MYC. We find that BRD9 is dispensable for human induced pluripotent stem cells under primed but not under naive conditions. Mechanistically, BRD9 inhibition downregulates fibroblast-related genes and decreases chromatin accessibility at somatic enhancers. BRD9 maintains the expression of transcriptional regulators MN1 and ZBTB38, both of which impede reprogramming. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers chromatin-based barriers to reprogramming.",

author = "Kenan Sevin{\c c} and Sevin{\c c}, \{G{\"u}lben G{\"u}rhan\} and Cavga, \{Ay{\c s}e Derya\} and Martin Philpott and Simge Kelek{\c c}i and Hazal Can and Cribbs, \{Adam P.\} and Yıldız, \{Abdullah Burak\} and Alperen Yılmaz and Ayar, \{Enes Sefa\} and Arabacı, \{Dil{\c s}ad H.\} and Dunford, \{James E.\} and Deniz Ata and Sigua, \{Logan H.\} and Jun Qi and Udo Oppermann and Onder, \{Tamer T.\}",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = dec,

day = "13",

doi = "10.1016/j.stemcr.2022.10.005",

language = "English",

volume = "17",

pages = "2629--2642",

journal = "Stem Cell Reports",

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Sevinç, K, Sevinç, GG, Cavga, AD, Philpott, M, Kelekçi, S, Can, H, Cribbs, AP, Yıldız, AB, Yılmaz, A, Ayar, ES, Arabacı, DH, Dunford, JE, Ata, D, Sigua, LH, Qi, J, Oppermann, U & Onder, TT 2022, 'BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming', Stem Cell Reports, vol. 17, no. 12, pp. 2629-2642. https://doi.org/10.1016/j.stemcr.2022.10.005

TY - JOUR

T1 - BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming

AU - Sevinç, Kenan

AU - Sevinç, Gülben Gürhan

AU - Cavga, Ayşe Derya

AU - Philpott, Martin

AU - Kelekçi, Simge

AU - Can, Hazal

AU - Cribbs, Adam P.

AU - Yıldız, Abdullah Burak

AU - Yılmaz, Alperen

AU - Ayar, Enes Sefa

AU - Arabacı, Dilşad H.

AU - Dunford, James E.

AU - Ata, Deniz

AU - Sigua, Logan H.

AU - Qi, Jun

AU - Oppermann, Udo

AU - Onder, Tamer T.

PY - 2022/12/13

Y1 - 2022/12/13

N2 - Epigenetic reprogramming to pluripotency requires extensive remodeling of chromatin landscapes to silence existing cell-type-specific genes and activate pluripotency genes. ATP-dependent chromatin remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of recently identified Bromodomain-containing protein 9 (BRD9) and the associated non-canonical BRG1-associated factors (ncBAF) complex in reprogramming remains unknown. Here, we show that genetic or chemical inhibition of BRD9, as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, increase human somatic cell reprogramming efficiency and can replace KLF4 and c-MYC. We find that BRD9 is dispensable for human induced pluripotent stem cells under primed but not under naive conditions. Mechanistically, BRD9 inhibition downregulates fibroblast-related genes and decreases chromatin accessibility at somatic enhancers. BRD9 maintains the expression of transcriptional regulators MN1 and ZBTB38, both of which impede reprogramming. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers chromatin-based barriers to reprogramming.

AB - Epigenetic reprogramming to pluripotency requires extensive remodeling of chromatin landscapes to silence existing cell-type-specific genes and activate pluripotency genes. ATP-dependent chromatin remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of recently identified Bromodomain-containing protein 9 (BRD9) and the associated non-canonical BRG1-associated factors (ncBAF) complex in reprogramming remains unknown. Here, we show that genetic or chemical inhibition of BRD9, as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, increase human somatic cell reprogramming efficiency and can replace KLF4 and c-MYC. We find that BRD9 is dispensable for human induced pluripotent stem cells under primed but not under naive conditions. Mechanistically, BRD9 inhibition downregulates fibroblast-related genes and decreases chromatin accessibility at somatic enhancers. BRD9 maintains the expression of transcriptional regulators MN1 and ZBTB38, both of which impede reprogramming. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers chromatin-based barriers to reprogramming.

UR - https://www.scopus.com/pages/publications/85143850388

U2 - 10.1016/j.stemcr.2022.10.005

DO - 10.1016/j.stemcr.2022.10.005

M3 - Article

C2 - 36332631

AN - SCOPUS:85143850388

SN - 2213-6711

VL - 17

SP - 2629

EP - 2642

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 12

ER -

BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming

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