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HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs (ChIP-Seq)

ABSTRACT: Despite the fundamental roles to cell fates determination in all metazoans, the mechanism by which the TGF-β family signaling is interpreted into spatial and temporal manner and multiple cell fates is still elusive. The cell context dependent function of TGF-β signaling largely relies on the transcriptional regulation centered by SMAD proteins. Here, we discovered that the DNA-repair related protein, HMCES contributes to early development by maintaining the nodal/activin or BMP signaling related transcriptome homeostasis. HMCES is a R-SMAD proteins binding partner that co-localizes with R-SMADs at active histone marks. However, HMCES chromatin occupancy is independent of nodal/activin or BMP signaling. Mechanically, HMCES exerts its transcriptional regulation role by counteracting R-SMAD proteins association with chromatin. In Xenopus embryo, hmces-KD causes dramatic development defects with altered left-right axis asymmetry along with increasing expression of lefty1. In sum, we disclosed the novel transcriptional regulatory function of HMCES integrated in TGF-β family signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE186222 | GEO | 2022/09/14

REPOSITORIES: GEO

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HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs (RNA-Seq)

Project description:Despite the fundamental roles to cell fates determination in all metazoans, the mechanism by which the TGF-β family signaling is interpreted into spatial and temporal manner and multiple cell fates is still elusive. The cell context dependent function of TGF-β signaling largely relies on the transcriptional regulation centered by SMAD proteins. Here, we discovered that the DNA-repair related protein, HMCES contributes to early development by maintaining the nodal/activin or BMP signaling related transcriptome homeostasis. HMCES is a R-SMAD proteins binding partner that co-localizes with R-SMADs at active histone marks. However, HMCES chromatin occupancy is independent of nodal/activin or BMP signaling. Mechanically, HMCES exerts its transcriptional regulation role by counteracting R-SMAD proteins association with chromatin. In Xenopus embryo, hmces-KD causes dramatic development defects with altered left-right axis asymmetry along with increasing expression of lefty1. In sum, we disclosed the novel transcriptional regulatory function of HMCES integrated in TGF-β family signaling.

2022-09-14 | GSE186223 | GEO

A fine-tuned regulation of Bmp2 by Nodal/TGFβ signalling induced lncRNA-Smad7

Project description:The transforming growth factor beta (TGF-β) superfamily proteins are potent regulators of cellular development and differentiation. Long non-coding RNAs (lncRNAs) play widespread roles in spatial-temporal regulation of early development. However, the roles of lncRNAs regulated by nodal/TGF-β signaling is still elusive. Here, we showed a nodal-driven Smad induced lncRNA in mouse embryonic stem cells (mESCs), lncRNA-Smad7, which is divergently transcribed to Smad7, regulates cell fate determination through repressing Bmp2. Depletion of lncRNA-Smad7 dramatically impairs cardiomyocyte differentiation in mESCs. Moreover, LncRNA-Smad7 represses Bmp2 expression and binds at the promoter region of Bmp2. Importantly, knock-down Bmp2 rescues the defect of cardiomyocyte differentiation. Hence, we showed that lncRNA-Smad7 is antagonistic to BMP signaling in mESCs. Furthermore, lncRNA-Smad7 regulates cell fate determination between osteocytes and myocytes formation in C2C12 cells by repressing Bmp2. Thus, we provide new insights regarding the antagonistic effects between nodal/TGF-β and BMP signaling via lncRNA-Smad7.

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Quantitative proteomics of the SMAD transcription factor family reveals IPO5 as a BMP Receptor-SMAD specific importin

Project description:Gene-specific transcription factors (GSTFs) control of gene transcription by DNA binding and specific protein complex recruitment, which regulates promoter accessibility for transcription initiation by RNA polymerase II. GSTFs that are frequently mutated in colon and rectal carcinomas are Suppressor of Mothers Against Decapentaplegic 2 (SMAD2) and SMAD4, which play an important role in the TGF-β signaling pathways controlling cell fate and proliferation (ref.). The SMAD protein family is a diverse and it can be divided into three subclasses: receptor activated SMADs, inhibitory SMADs and the common SMAD4 co-activator. To study protein interactors of the SMAD protein family we generated a quantitative proteomics pipeline that allows for inducible expression of GFP-tagged SMAD proteins followed by affinity purification and MS analysis. The nuclear importin IPO5 was identified as a novel interacting protein of SMAD1. Overexpression of IPO5 shows forced BMP R-SMAD nuclear localization confirming a functional relationship between BMP but not TGF-β R-SMADs and IPO5. Finally we provide evidence that the length of the lysine stretch in the NLS is involved in importin selection.

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RNA-seq analysis to profile TGF-beta/Activin signaling-dependent gene expression in Drosophila larval skeletal muscle

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HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs

Project description:HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs

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Project description:Members of the transforming growth factor (TGF)-β superfamily play essential roles in the pluripotency, self-renewal, and differentiation of embryonic stem cells. While bone morphogenic proteins maintain pluripotency of undifferentiated mouse ES cells, the role of Activin/Nodal signaling is less clear. To determine the target genes of Activin/Nodal-Smad2 signaling in undifferentiated embryonic stem cells, changes in gene expression were examined following stimulation with recombinant Activin (2 hours) or after inhibition of Activin/Nodal with SB431542 (24 hours) using defined media culture conditions with LIF and 20 ng/mL BMP4. SB431542 is a specific inhibitor of ALK4/5/7 receptors and antagonizes both Activin and Nodal signaling. Via western analysis, Activin stimulation increased pSmad2 in ES cells after 2 hours, and treatment with SB431542 for 24 hours virtually eliminated pSmad2. Total Smad2 expression remained unchanged through these manipulations. RNA from cells treated with Activin or SB431542 was extracted by standard methods with Qiagen RNeasy columns. The RNA was analyzed with the Mouse Genome 430A Array from Affymetrix. Samples were performed in duplicate, and RNA from cells treated with Activin or SB431542 was compared to untreated embryonic stem cells.

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Activin A in Combination with ERK1/2 MAPK Pathway Inhibition Sustains Propagation of Mouse Embryonic Stem Cells

Project description:Activin/Nodal/TGF-β signaling pathway plays a major role in maintaining mouse epiblast stem cells (mEpiSCs). The mEpiSC medium which contains Activin A and bFGF induces differentiation of mouse embryonic stem cells (mESCs) to mEpiSC. Here we show that Activin A also has an ability to efficiently propagate mESCs without differentiation to mEpiSCs when combined with a MEK inhibitor PD0325901. mESCs cultured in Activin+PD retained high-level expression of naive pluripotency-related transcription factors. Genome-wide analysis revealed that the gene expression profile of mESCs cultured in Activin+PD resembles that of mESCs cultured in 2i. mESCs cultured in Activin+PD also showed features which are related to naive pluripotency of mESCs, including the preferential usage of the Oct4 distal enhancer and the self-renewal response to Wnt pathway activation. Our finding reveals a role of Activin/Nodal/TGF-β signaling in stabilizing self-renewal gene regulatory networks in mESCs. To compare the gene expression patterns of mESCs cultured in Activin+PD, 2i and LIF+BMP4 and mEpiSCs, we performed genome-wide gene expression analysis by using Affymetrix GeneChip oligonucleotide microarrays

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Project description:Bone morphogenetic protein (BMP) signaling is known to support differentiation of human embryonic stem cells (hESCs) into mesoderm and extraembryonic lineages, whereas other signaling pathways can largely influence this lineage specification. Here, we set out to reinvestigate the influence of ACTIVIN/NODAL and fibroblast growth factor (FGF) pathways on the lineage choices made by hESCs during BMP4-driven differentiation. We show that BMP activation, coupled with inhibition of both ACTIVIN/NODAL and FGF signaling, induces differentiation of hESCs, specifically to M-NM-2hCG hormone-secreting multinucleated syncytiotrophoblast and does not support induction of embryonic and extraembryonic lineages, extravillous trophoblast, and primitive endoderm. It has been previously reported that FGF2 can switch BMP4-induced hESC differentiation outcome to mesendoderm. Here, we show that FGF inhibition alone, or in combination with either ACTIVIN/NODAL inhibition or BMP activation, supports hESC differentiation to hCG-secreting syncytiotrophoblast. We show that the inhibition of the FGF pathway acts as a key in directing BMP4-mediated hESC differentiation to syncytiotrophoblast. Human embryonic Stem Cells (hESCs) were treated under defined conditions (N2B27) with BMP4 (B), SB431542 (SB) (ACTIVIN/NODAL inhibitor), SU5402 (SU) (FGFR1 inhibitor), FGF2 (F) either alone or in various combinations as mentioned, followed by isolation of total RNA.

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HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs (ChIP-Seq)

Project description:HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs (ChIP-Seq)

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HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs (RNA-Seq)

Project description:HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs (RNA-Seq)

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