scholarly journals Chromatin remodeler Brahma safeguards canalization in cardiac mesoderm differentiation

2020 ◽  
Author(s):  
Swetansu K. Hota ◽  
Andrew P. Blair ◽  
Kavitha S. Rao ◽  
Kevin So ◽  
Aaron M. Blotnick ◽  
...  
Keyword(s):  
Cell Fate ◽  
Chromatin Remodeling ◽  
De Novo ◽  
Embryonic Stem ◽  
Mesoderm Induction ◽  
Chromatin Remodeling Complex ◽  
Atpase Gene ◽  
Neurogenic Factor ◽  
Well Differentiated ◽  
Cardiac Mesoderm

SUMMARYDifferentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1–4. Canalization is essential for stabilizing cell fate, but the mechanisms underlying robust canalization are unclear. Here we show that deletion of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm (encoding Brahma) results in a radical identity switch during directed cardiogenesis of mouse embryonic stem cells (ESCs). Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells subsequently shifted identities, predominantly becoming neural precursors, violating germ layer assignment. Trajectory inference showed sudden acquisition of non-mesodermal identity in Brm-null cells, consistent with a new transition state inducing a fate switch referred to as a saddle-node bifurcation3,4. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of the neurogenic factor POU3F1 and preventing expression of the neural suppressor REST. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction, repressing Pou3f1 and re-establishing a cardiogenic chromatin landscape. Our results reveal BRM as a compensable safeguard for fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory that must be safeguarded, with implications in development and disease.

scholarly journals SWI/SNF chromatin remodeling complex is required for initiation of sex-dependent differentiation in mouse germline

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Toshiaki Ito ◽  
Atsuki Osada ◽  
Masami Ohta ◽  
Kana Yokota ◽  
Akira Nishiyama ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Germ Cells ◽  
De Novo ◽  
Primordial Germ Cells ◽  
Strand Break ◽  
Conditional Knockout ◽  
Dna Hypomethylation ◽  
Aberrant Expression ◽  
Chromatin Remodeling Complex ◽  
Expression Of Genes

AbstractSexual reproduction involves the creation of sex-dependent gametes, oocytes and sperm. In mammals, sexually dimorphic differentiation commences in the primordial germ cells (PGCs) in embryonic gonads; PGCs in ovaries and testes differentiate into meiotic primary oocytes and mitotically quiescent prospermatogonia, respectively. Here, we show that the transition from PGCs to sex-specific germ cells was abrogated in conditional knockout mice carrying a null mutation of Smarcb1 (also known as Snf5) gene, which encodes a core subunit of the SWI/SNF chromatin remodeling complex. In female mutant mice, failure to upregulate meiosis-related genes resulted in impaired meiotic entry and progression, including defects in synapsis formation and DNA double strand break repair. Mutant male mice exhibited delayed mitotic arrest and DNA hypomethylation in retrotransposons and imprinted genes, resulting from aberrant expression of genes related to growth and de novo DNA methylation. Collectively, our results demonstrate that the SWI/SNF complex is required for transcriptional reprogramming in the initiation of sex-dependent differentiation of germ cells.

scholarly journals DNA methyltransferase-3–dependent nonrandom template segregation in differentiating embryonic stem cells

2013 ◽  
Vol 203 (1) ◽  
pp. 73-85 ◽  
Author(s):  
Christian Elabd ◽  
Wendy Cousin ◽  
Robert Y. Chen ◽  
Marc S. Chooljian ◽  
Joey T. Pham ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Molecular Mechanism ◽  
Cell Fate ◽  
Dna Methyltransferase ◽  
Daughter Cell ◽  
De Novo ◽  
Embryonic Stem ◽  
Fundamental Property ◽  
Dna Strands

Asymmetry of cell fate is one fundamental property of stem cells, in which one daughter cell self-renews, whereas the other differentiates. Evidence of nonrandom template segregation (NRTS) of chromosomes during asymmetric cell divisions in phylogenetically divergent organisms, such as plants, fungi, and mammals, has already been shown. However, before this current work, asymmetric inheritance of chromatids has never been demonstrated in differentiating embryonic stem cells (ESCs), and its molecular mechanism has remained unknown. Our results unambiguously demonstrate NRTS in asymmetrically dividing, differentiating human and mouse ESCs. Moreover, we show that NRTS is dependent on DNA methylation and on Dnmt3 (DNA methyltransferase-3), indicating a molecular mechanism that regulates this phenomenon. Furthermore, our data support the hypothesis that retention of chromatids with the “old” template DNA preserves the epigenetic memory of cell fate, whereas localization of “new” DNA strands and de novo DNA methyltransferase to the lineage-destined daughter cell facilitates epigenetic adaptation to a new cell fate.

scholarly journals Definition of germ cell lineage alternative splicing programs reveals a critical role for Quaking in specifying cardiac cell fate

2020 ◽  
Author(s):  
W. Samuel Fagg ◽  
Naiyou Liu ◽  
Ulrich Braunschweig ◽  
Xiaoting Chen ◽  
Steven G. Widen ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cell Fate ◽  
Rna Binding ◽  
Cardiac Development ◽  
Splice Variants ◽  
Critical Role ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Definitive Endoderm ◽  
Cardiac Mesoderm

SummaryAlternative splicing is critical for animal ontogeny; however, its role in the earliest developmental decision, the specification of the three embryonic germ layers, is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived definitive endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage, with the largest splicing differences observed between definitive endoderm and cardiac mesoderm. Integrative multiomics analyses predict lineage-specific RNA binding protein regulators, including a prominent role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI in hESCs disrupts the cardiac mesoderm-associated alternative splicing program and formation of myocytes, likely in part through reduced expression of BIN1 splice variants linked to cardiac development. Our results thus uncover alternative splicing programs associated with the three germ lineages and highlight an important role for QKI and its target transcripts in the formation of cardiac mesoderm.

scholarly journals BAF250B-Associated SWI/SNF Chromatin-Remodeling Complex Is Required to Maintain Undifferentiated Mouse Embryonic Stem Cells

Stem Cells ◽  
2008 ◽  
Vol 26 (5) ◽  
pp. 1155-1165 ◽  
Author(s):  
Zhijiang Yan ◽  
Zhong Wang ◽  
Lioudmila Sharova ◽  
Alexei A. Sharov ◽  
Chen Ling ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Chromatin Remodeling ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Chromatin Remodeling Complex

scholarly journals SWI/SNF chromatin remodeling controls Notch-responsive enhancer accessibility

2018 ◽  
Author(s):  
Zoe Pillidge ◽  
Sarah J Bray
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Transcriptional Response ◽  
Histone Chaperones ◽  
Chromatin Remodelers ◽  
Cell Fate Decisions ◽  
Chromatin Remodeling Complex ◽  
Brahma Complex

AbstractNotch signaling plays a key role in many cell fate decisions during development by directing different gene expression programs via the transcription factor CSL, known as Su(H) in Drosophila. Which target genes are responsive to Notch signaling is influenced by the chromatin state of enhancers, yet how this is regulated is not fully known. Detecting an increase in the histone variant H3.3 in response to Notch signaling, we tested which chromatin remodelers or histone chaperones were required for the changes in enhancer accessibility to Su(H) binding. This revealed a crucial role for the Brahma SWI/SNF chromatin remodeling complex in conferring enhancer accessibility and enabling the transcriptional response. The Notch-responsive regions had high levels of nucleosome turnover which were dependent on the Brahma complex, increased with Notch signaling and primarily involved histone H3.3. Together these results highlight the importance of SWI/SNF-mediated nucleosome turnover in rendering enhancers responsive to Notch.

scholarly journals Disabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory

2021 ◽  
Vol 118 (38) ◽  
pp. e2109475118
Author(s):  
Masaki Kinoshita ◽  
Meng Amy Li ◽  
Michael Barber ◽  
William Mansfield ◽  
Sabine Dietmann ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Fate ◽  
De Novo ◽  
Es Cells ◽  
Embryonic Stem ◽  
Dna Methyltransferases ◽  
Bhlh Transcription Factor ◽  
Mammalian Development

Genome remethylation is essential for mammalian development but specific reasons are unclear. Here we examined embryonic stem (ES) cell fate in the absence of de novo DNA methyltransferases. We observed that ES cells deficient for both Dnmt3a and Dnmt3b are rapidly eliminated from chimeras. On further investigation we found that in vivo and in vitro the formative pluripotency transition is derailed toward production of trophoblast. This aberrant trajectory is associated with failure to suppress activation of Ascl2. Ascl2 encodes a bHLH transcription factor expressed in the placenta. Misexpression of Ascl2 in ES cells provokes transdifferentiation to trophoblast-like cells. Conversely, Ascl2 deletion rescues formative transition of Dnmt3a/b mutants and improves contribution to chimeric epiblast. Thus, de novo DNA methylation safeguards against ectopic activation of Ascl2. However, Dnmt3a/b-deficient cells remain defective in ongoing embryogenesis. We surmise that multiple developmental transitions may be secured by DNA methylation silencing potentially disruptive genes.

scholarly journals Ribosome and Translational Control in Stem Cells

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 497 ◽  
Author(s):  
Mathieu Gabut ◽  
Fleur Bourdelais ◽  
Sébastien Durand
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Translational Control ◽  
Ribosome Biogenesis ◽  
Adult Stem Cells ◽  
Embryonic Stem ◽  
Cell Homeostasis ◽  
Cell Functions

Embryonic stem cells (ESCs) and adult stem cells (ASCs) possess the remarkable capacity to self-renew while remaining poised to differentiate into multiple progenies in the context of a rapidly developing embryo or in steady-state tissues, respectively. This ability is controlled by complex genetic programs, which are dynamically orchestrated at different steps of gene expression, including chromatin remodeling, mRNA transcription, processing, and stability. In addition to maintaining stem cell homeostasis, these molecular processes need to be rapidly rewired to coordinate complex physiological modifications required to redirect cell fate in response to environmental clues, such as differentiation signals or tissue injuries. Although chromatin remodeling and mRNA expression have been extensively studied in stem cells, accumulating evidence suggests that stem cell transcriptomes and proteomes are poorly correlated and that stem cell properties require finely tuned protein synthesis. In addition, many studies have shown that the biogenesis of the translation machinery, the ribosome, is decisive for sustaining ESC and ASC properties. Therefore, these observations emphasize the importance of translational control in stem cell homeostasis and fate decisions. In this review, we will provide the most recent literature describing how ribosome biogenesis and translational control regulate stem cell functions and are crucial for accommodating proteome remodeling in response to changes in stem cell fate.

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