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

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

doi:10.1016/j.stemcr.2022.10.005

Cited by 9 publications

(5 citation statements)

References 60 publications

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“…The last was surprising as Brdt is expressed at low levels in both EpiSCs and ESCs ( Figure 1a ). BRD9 has previously been implicated in controlling human pluripotency through a non-canonical BAF protein complex 26 , and its inhibition promoted the conversion of ESCs to an EpiSC-like state 25 . Our data suggests that reduced Brd9 promotes the conversion of EpiSCs to ESCs.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we set out to understand the epigenetic barriers that prevent the cell fate conversion from primed EpiSCs to naïve ESCs. We focused on the bromodomain family of epigenetic co-factors as several family members have been implicated in cell type conversions [25][26][27] . We discovered a role for the bromodomaincontaining protein BRD8 in blocking cell-type conversions.…”

Section: Introductionmentioning

confidence: 99%

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BRD8 guards the pluripotent state by sensing and maintaining histone acetylation

Sun,

Fu,

Xiao

et al. 2024

Preprint

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Epigenetic control of cell fates is a critical determinant to maintain cell type stability and permissive differentiation. However, the epigenetic control mechanisms are not well understood. Here, we show that the histone acetyltransferase reader protein BRD8 impairs the conversion of primed mouse EpiSCs (epiblast stem cells) to naive mouse ESCs (embryonic stem cells). BRD8 works by maintaining histone acetylation on promoters and transcribed gene bodies. BRD8 is responsible for maintaining open chromatin at somatic genes, and histone acetylation at naive-specific genes. When Brd8 expression was reduced, chromatin accessibility was unchanged, but histone acetylation at primed-specific genes was reduced. Conversely, naive-specific genes had reduced repressive chromatin marks, and acquired accessible chromatin more rapidly during the cell type conversion. We show that this process requires active histone deacetylation to promote the conversion of primed to naive. Our data supports a model for BRD8 reading histone acetylation to accurately localize the genome-wide binding of the histone acetyltransferase KAT5. Overall, this study shows how the reading of the histone acetylation state by BRD8 maintains cell type stability.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BRD8 guards the pluripotent state by sensing and maintaining histone acetylation

Sun,

Fu,

Xiao

et al. 2024

Preprint

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“…These results suggested that BRD9 inhibition could induce differentiation of therapy-resistant CSCs into a more therapy-responsive population and thus could possibly sensitize PDAC cancers to conventional therapy. BRD9 is a component of the non-canonical BAF chromatin remodelling complex (ncBAF) 35 and has recently been shown to constitute a barrier in reprogramming of somatic cells to induced pluripotent stem cells 36 . The catalytic component SMARCA4 of the BAF complex regulates stem cell properties in pediatric gliomas and provides a possible therapeutic angle in glioblastoma treatment 37 .…”

Section: Resultsmentioning

confidence: 99%

BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma

Feng

Cai

Pook

et al. 2023

Preprint

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The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signalling pathway. Inhibition and genetic ablation of BDR9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumours from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

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“…During the initiation stage, cells undergo mesenchymal-to-epithelial (MET) transition, characterized by the repression of transforming factor beta (TGFbeta), activation of bone morphogenic protein (BMP), stress activated of mitogen-activated protein kinase (MAPK) and p38 MAPK signaling, and extensive remodeling of chromatin ( Maherali and Hochedlinger, 2009 ; Li et al, 2010 ; Chen et al, 2011 ; Hu et al, 2014 ; Neganova et al, 2016 ; Neganova et al, 2017 ; Francesconi et al, 2019 ; Meir and Li, 2021 ). A number of epigenetic regulators of chromatin, including DOT1L methyltransferase, histone demethylase LSD1, CBP/EP300 bromodomains, bromodomain-containing protein BRD9, histone chaperone CAF-1, BET family proteins, RNA Pol II regulator RPAP1, SUMO modification, chromatin regulator FACT, histone deacetylases HDACs, methyltransferase Setdb1, and the TF TRIM28, act as potent barriers to reprogramming ( Cheloufi et al, 2015 ; Wei et al, 2015 ; Shao et al, 2016 ; Sun et al, 2016 ; Miles et al, 2017 ; Cossec et al, 2018 ; Kolundzic et al, 2018 ; Lynch et al, 2018 ; Ebrahimi et al, 2019 ; Sevinc et al, 2022 ). Some of these factors maintain somatic cell gene expression programs, and some suppress the MET transition, mainly during the initial stage of reprogramming.…”

Section: Main Characteristics Of the Stages Of Reprogramming Toward P...mentioning

confidence: 99%

Metabolic control of induced pluripotency

Sinenko,

Tomilin

2024

Front. Cell Dev. Biol.

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Pluripotent stem cells of the mammalian epiblast and their cultured counterparts—embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs)—have the capacity to differentiate in all cell types of adult organisms. An artificial process of reactivation of the pluripotency program in terminally differentiated cells was established in 2006, which allowed for the generation of induced pluripotent stem cells (iPSCs). This iPSC technology has become an invaluable tool in investigating the molecular mechanisms of human diseases and therapeutic drug development, and it also holds tremendous promise for iPSC applications in regenerative medicine. Since the process of induced reprogramming of differentiated cells to a pluripotent state was discovered, many questions about the molecular mechanisms involved in this process have been clarified. Studies conducted over the past 2 decades have established that metabolic pathways and retrograde mitochondrial signals are involved in the regulation of various aspects of stem cell biology, including differentiation, pluripotency acquisition, and maintenance. During the reprogramming process, cells undergo major transformations, progressing through three distinct stages that are regulated by different signaling pathways, transcription factor networks, and inputs from metabolic pathways. Among the main metabolic features of this process, representing a switch from the dominance of oxidative phosphorylation to aerobic glycolysis and anabolic processes, are many critical stage-specific metabolic signals that control the path of differentiated cells toward a pluripotent state. In this review, we discuss the achievements in the current understanding of the molecular mechanisms of processes controlled by metabolic pathways, and vice versa, during the reprogramming process.

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

Cited by 9 publications

References 60 publications

BRD8 guards the pluripotent state by sensing and maintaining histone acetylation

BRD8 guards the pluripotent state by sensing and maintaining histone acetylation

BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma

Metabolic control of induced pluripotency

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