Splicing and Chromatin Factors Jointly Regulate Epidermal Differentiation

Tanis, Sabine E.J.; Jansen, Pascal W.T.C.; Zhou, Huiqing; Heeringen, Simon J. van; Vermeulen, Michiel; Kretz, Markus; Mulder, Klaas W.

doi:10.1016/j.celrep.2018.10.017

Cited by 24 publications

(26 citation statements)

References 47 publications

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“…Using multi-dimensional readouts, we found strong phenotypic similarities between Ncor1 and Oct4 depletion. Such phenotypic similarities often reflect functional interactions [23,24,26]. Our analyses indicate that NCOR1 and OCT4 co-bind a group of promoters that are also bound by c-MYC in early reprogramming cell populations.…”

Section: Discussionmentioning

confidence: 68%

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NCOR1 and OCT4 Facilitate Early Reprogramming by Co-Suppressing Fibroblast Gene Expression

Peñalosa-Ruiz

Mulder

Veenstra

2019

Preprint

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Reprogramming somatic cells to induced pluripotent stem cells (iPSC) succeeds only in a small fraction of cells within the population. Reprogramming occurs in distinctive stages, each facing its own bottlenecks. It initiates with overexpression of transcription factors OCT4, SOX2, KLF4 and c-MYC (OSKM) in somatic cells such as mouse embryonic fibroblasts (MEFs). OSKM bind chromatin, silencing the somatic identity and starting the stepwise reactivation of the pluripotency program. However, inefficient suppression of the somatic lineage leads to unwanted epigenetic memory from the tissue of origin, even in successfully generated iPSCs. Thus, it is essential to shed more light on chromatin regulators and processes involved in dissolving the somatic identity. Recent work characterized the role of transcriptional co-repressors NCOR1 and NCOR2 (also known as NCoR and SMRT), showing that they cooperate with c-MYC to silence pluripotency genes during late reprogramming stages. NCOR1/NCOR2 were also proposed to be involved in silencing fibroblast identity, however it is unclear how this happens. Here, we shed light on the role of NCOR1 in early reprogramming. We show that siRNA-mediated ablation of NCOR1 and OCT4 results in very similar phenotypes, including transcriptomic changes and highly correlated high content colony phenotypes. . Both NCOR1 and OCT4 bind to promoters co-occupied by c-MYC in MEFs. During early reprogramming, downregulation of one group of somatic MEF-expressed genes requires both NCOR1 and OCT4, whereas another group of MEF-expressed genes is downregulated by NCOR1 but not OCT4. Our data suggest that NCOR1, assisted by OCT4 and c-MYC, facilitates transcriptional inactivation of genes with high expression in MEFs, which need to be suppressed to bypass an early reprogramming block. This way, NCOR1 facilitates early reprogramming progression.

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Section: Discussionmentioning

confidence: 68%

“…1A). We have previously identified functional interactions from knockdowns showing similar phenotypes [23,24,26]. Using this rationale, we compared knockdown-toknockdown correlations based on high-content phenotypes and also based on transcriptomes ( Fig.…”

Section: High Content Screening Reveals Early Reprogramming Disruptiomentioning

confidence: 99%

NCOR1 and OCT4 Facilitate Early Reprogramming by Co-Suppressing Fibroblast Gene Expression

Peñalosa-Ruiz

Mulder

Veenstra

2019

Preprint

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“…A zinc-finger protein, ZMAT2 is expressed in multiple tissues including high expression in the brain (GTEx data). In epidermal cells it is know to be an interactor of the pre-spliceosome that is required to keep cells in an undifferentiated, proliferative state (Tanis et al 2018). It has also been reported by Jaffe et al to be significantly developmentally regulated (Jaffe et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Schizophrenia Risk Alleles Often Affect the Expression of Many Genes and Each Gene May Have a Different Effect on The Risk; A Mediation Analysis

Peng

Bader

Avramopoulos

2020

Preprint

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Variants identified by Genome wide association studies (GWAS) are often expression quantitative trait loci (eQTLs), suggesting they are proxies or are themselves regulatory.Additionally eQTL analyses show that variants often affect more than one gene. Lacking data on many tissue types, developmental time points and homogeneous cell types, the extent of this one-to-many relationship is underestimated. This raises questions on whether a disease eQTL target gene explains the genetic association or is a by-stander.It also puts into question the direction of the effect of a gene's expression on the risk, since the many genes regulated by the same variant may have opposing effects, imperfectly balancing each other. We used two brain gene expression datasets (CommonMind and BrainSeq) for a mediation analysis of schizophrenia-associated variants. We find that indeed eQTL targets often mediate risk but the direction in which expression affects risk is often different from the direction in which the risk allele changes expression. Of 38 genes significant for mediation in both datasets 33 showed consistent direction (Chi 2 test P=6*10 -6 ) and for 15 of them (45%) the expression change associated with the risk allele was protective, which suggests the likely presence of other target genes with overriding effects. Our results identify specific risk mediating genes and suggest caution in interpreting the biological consequences of targeted modifications of gene expression, as not all eQTL targets may be relevant to disease and those that are might have different than expected directions.

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“…Combinatorial mechanisms have been proposed in which hnRNPs help to position splicing factors in the spliceosome and to block splice sites (Heinrich et al, 2009;Grillari et al, 2009;Howard et al, 2018). Other splicing factors, such as ZMAT2, fine-tune splicing by causing rearrangement to the spliceosome (Tanis et al, 2018). We speculate that chromatin remodelling factors also influence the spatial association of general splicing machinery with RNA; by recruiting, stabilising, and evicting splicing factors, to rearrange their interactions at the exons to fine-tune the splicing result ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

The SWI/SNF subunits BRG1 affects alternative splicing by changing RNA binding factor interactions with RNA

Mackowiak

Guo

et al. 2019

Preprint

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BRG1 and BRM are ATPase core subunits of the human SWI/SNF chromatin remodelling complexes. The function of the SWI/SNF complexes in transcriptional initiation has been well studied, while a function in alternative splicing has only been studied for a few cases for BRM-containing SWI/SNF complexes. Here, we have expressed BRG1 in C33A cells, a BRG1 and BRM-deficient cell line, and we have analysed the effects on the transcriptome by RNA sequencing. We have shown that BRG1 expression affects the splicing of a subset of genes. For some, BRG1 expression favours exon inclusion and for others, exon skipping. Some of the changes in alternative splicing induced by BRG1 expression do not require the ATPase activity of BRG1. Among the exons regulated through an ATPase-independent mechanism, the included exons had signatures of high GC-content and lacked a positioned nucleosome at the exon. By investigating three genes in which the expression of either wild-type BRG1 or a BRG1-ATPase-deficient variant favoured exon inclusion, we showed that expression of the ATPases promotes the local recruitment of RNA binding factors to chromatin and RNA in a differential manner. The hnRNPL, hnRNPU and SAM68 proteins associated to chromatin in C33A cells expressing BRG1 or BRM, but their association with RNA varied. We propose that SWI/SNF can regulate alternative splicing by interacting with splicing-RNA binding factor and altering their binding to the nascent pre-mRNA, which changes RNP structure. Author summarySplicing, in particular alternative splicing, is a combinatorial process which involves splicing factor complexes and many RNA binding splicing regulatory proteins in different constellations. Most splicing events occur during transcription, which also makes the DNA sequence, the chromatin state and the transcription rate at the exons important components that influence the splicing outcome. We show here that the ATP-dependent chromatin remodelling complex SWI/SNF influences the interactions of splicing regulatory factors with RNA during transcription on certain exons that have a high GC-content. The splicing on this type of exon rely on the ATPase BRG1 and favour inclusion of alternative exons in an ATP-independent manner. SWI/SNF complexes are known to alter the chromatin structure at promoters in transcription initiation, and have been previously shown to alter the transcription rate or nucleosome position in splicing. Our results suggests a further mechanism for chromatin remodelling proteins in splicing: to change the interaction patterns of RNA binding splicing regulatory factors at alternative exons to alter the splicing outcome. Biegel JA, Busse TM, Weissman BE. SWI/SNF chromatin remodeling complexes and cancer. Am Lynch KW. Global analysis of physical and functional RNA targets of hnRNP L reveals distinct sequence and epigenetic features of repressed and enhanced exons. :52. Custódio N, Carmo-Fonseca M. Co-transcriptional splicing and the CTD code. Crit Rev Biochem Mol Biol. 2016 Sep;51(5):395-411. De Conti L, Baralle M...

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Splicing and Chromatin Factors Jointly Regulate Epidermal Differentiation

Cited by 24 publications

References 47 publications

NCOR1 and OCT4 Facilitate Early Reprogramming by Co-Suppressing Fibroblast Gene Expression

NCOR1 and OCT4 Facilitate Early Reprogramming by Co-Suppressing Fibroblast Gene Expression

Schizophrenia Risk Alleles Often Affect the Expression of Many Genes and Each Gene May Have a Different Effect on The Risk; A Mediation Analysis

The SWI/SNF subunits BRG1 affects alternative splicing by changing RNA binding factor interactions with RNA

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