esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function

Jeon

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

Germinal center (GC) reaction is crucial in adaptive immune responses. The formation of GC is coordinated by the expression of specific genes including Blimp-1 and Bcl-6. Although gene expression is critically influenced by the status of chromatin structure, little is known about the role of chromatin remodeling factors for regulation of GC formation. Here, we show that the SWI/SNF chromatin remodeling complex is required for GC reactions. Mice lacking Srg3/mBaf155, a core component of the SWI/SNF complex, showed impaired differentiation of GC B and follicular helper T cells in response to T cell-dependent antigen challenge. The SWI/SNF complex regulates chromatin structure at the Blimp-1 locus and represses its expression by interacting cooperatively with Bcl-6 and corepressors. The defect in GC reactions in mice lacking Srg3 was due to the derepression of Blimp-1 as supported by genetic studies with Blimp-1–ablated mice. Hence, our study identifies the SWI/SNF complex as a key mediator in GC reactions by modulating Bcl-6–dependent Blimp-1 repression.

Section: Discussionmentioning

confidence: 99%

The SWI/SNF chromatin remodeling complex regulates germinal center formation by repressing Blimp-1 expression

Jeon

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

Journal of Biological Chemistry

“…The alteration of H3K27me3 levels may indicate a specific repressive role of BAF250a in ES cells. Although Brg1 deletion does not result in global H3K27me3 and H3K4me3 changes, H3K27me3 density decreased in Brg1-repressed genes and increased in Brg1-activated genes in Brg1 KO ES cells (33). These differences in histone modification changes in BAF250a KO and Brg1 KO ES cells reflect distinct functions exercised by esBAF components on histone modification regulations.…”

Section: Discussionmentioning

confidence: 79%

BAF250a Protein Regulates Nucleosome Occupancy and Histone Modifications in Priming Embryonic Stem Cell Differentiation

Lei

West

Yan

et al. 2015

Background: How BAF250a regulates nucleosome configuration in ES cells is not clear. Results: BAF250a regulates nucleosome occupancy and H3K27me3 to control gene expression during ES cell differentiation. Conclusion: BAF250a plays a key role in poised chromatin regulation. Significance: Understanding the mechanisms of chromatin remodeling in poised chromatin regulation provides epigenetic insights into ES cell differentiation.

Proc. Natl. Acad. Sci. U.S.A.

“…Successful development of ESC-based therapies, however, largely depends on our understanding of the genes and pathways that constitute the genetic network governing ESC self-renewal and differentiation. Focused functional studies, over the last two decades, have established Oct4, Sox2, and Nanog as the core transcription factors (18)(19)(20)(21), with epigenetic features (22)(23)(24), miRNAs (25)(26)(27), and telomere maintenance (28) playing key roles in the establishment and the maintenance of the pluripotent state in ESCs. Despite the elucidation of many genes and pathways critical for the maintenance of the pluripotent state, the mechanisms that coordinate the activities of master regulators, key signaling pathways, and epigenetic features remain poorly understood, owing largely to incomplete characterization of the genetic network underlying ESCs.…”

Section: Resultsmentioning

confidence: 99%

Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis

Cinghu

Yellaboina

Freudenberg

et al. 2014

Self Cite

Identification of genes associated with specific biological phenotypes is a fundamental step toward understanding the molecular basis underlying development and pathogenesis. Although RNAibased high-throughput screens are routinely used for this task, false discovery and sensitivity remain a challenge. Here we describe a computational framework for systematic integration of published gene expression data to identify genes defining a phenotype of interest. We applied our approach to rank-order all genes based on their likelihood of determining ES cell (ESC) identity. RNAi-mediated loss-of-function experiments on top-ranked genes unearthed many novel determinants of ESC identity, thus validating the derived gene ranks to serve as a rich and valuable resource for those working to uncover novel ESC regulators. Underscoring the value of our gene ranks, functional studies of our top-hit Nucleolin (Ncl), abundant in stem and cancer cells, revealed Ncl's essential role in the maintenance of ESC homeostasis by shielding against differentiation-inducing redox imbalance-induced oxidative stress. Notably, we report a conceptually novel mechanism involving a Nucleolin-dependent Nanog-p53 bistable switch regulating the homeostatic balance between self-renewal and differentiation in ESCs. Our findings connect the dots on a previously unknown regulatory circuitry involving genes associated with traits in both ESCs and cancer and might have profound implications for understanding cell fate decisions in cancer stem cells. The proposed computational framework, by helping to prioritize and preselect candidate genes for tests using complex and expensive genetic screens, provides a powerful yet inexpensive means for identification of key cell identity genes.C ell identity is governed by a set of key regulators, which maintain the gene expression program characteristic of that cell state while restricting the induction of alternate programs that could lead to a new cell state. Identification of cell identity genes is a fundamental step toward understanding the mechanisms that underlie cellular homeostasis, differentiation, development, and pathogenesis. RNAi-based high-throughput screening has become a widely used method for identification of new components of diverse biological processes, including signal transduction, cancer, and host cell responses to infection (1, 2). Genome-scale RNAi screens have led to identification of tumor suppressors (3), oncogenes (4), therapeutic targets (5), and regulators of ES cell (ESC) maintenance (6-10), tissue regeneration (11), viral infection (12), and antiviral response (13).Despite the success of RNAi screens, false discovery and sensitivity remain a significant and difficult problem to address, with surprisingly small overlap among screen hits from independent but related screens (1). For example, multiple genomescale RNAi screens for host proteins required for HIV infection/ replication resulted in a limited overlap among screen hits at the gene level (1). Similarly, screens performed in mous...