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Depletion of demethylase KDM6 enhances early neuroectoderm commitment of human ESCs through inhibiting WNT activation

ABSTRACT: Epigenetic modifications play a crucial role in learning, memory and neurogenesis, but the study of its role in early neuroectoderm commitment from pluripotent inner cell mass is relatively lack. Here we utilized the system of directed neuroectoderm differentiation from human embryonic stem cells and identified KDM6B, an enzyme responsible to erase H3K27me3, was the most upregulated enzyme of histone methylation during neuroectoderm differentiation by transcriptome analysis. We then constructed KDM6B-null embryonic stem cells and found strikingly, the cells with KDM6B knockout exhibited much higher neuroectoderm induction efficiency. Furthermore, we constructed a serial of embryonic stem cell lines knocking out the other H3K27 demethylase KDM6A, and depleting both KDM6A and KDM6B, respectively. These cell lines together confirmed KDM6 impeded early neuroectoderm commitment. By RNA-seq, we found a panel of WNT activation genes significantly downregulated while WNT inhibiting genes significantly upregulated upon depletion of KDM6. Functional rescue assayed that WNT agonist could abolish the differential neuroectoderm induction due to manipulating KDM6 demonstrated WNT was the major downstream of KDM6 during early neural induction. Taken together, our findings illustrated the important role of histone methylation modifier KDM6A and KDM6B in neuroectoderm differentiation and provided additional insights into the precise epigenetic regulation in different stage of neurogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE172312 | GEO | 2021/09/29

REPOSITORIES: GEO

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KDM6 Inhibition induces DNA Damage Response (DDR) during ESC Differentiation but not during self-renewal.

Project description:The discovery of the first histone demethylase in 2004 (LSD1/KDM1) opened new avenues for the understanding of how histone methylation impacts cellular functions. A great number of histone demethylases have been identified since, which are potentially linked to gene regulation as well as to stem cell self-renewal and differentiation. KDM6A/UTY and KDM6B/JMJD3 are both H3K27me3/2-specific histone demethylases, which are known to play a central role in regulation of posterior development, by regulating HOX gene expression. So far nothing is known about the role of histone lysine demethylases (KDMs) during early hematopoiesis. We are studying the role of KDM6A and KDM6B on self-renewal, global gene expression and on local and global chromatin states in embryonic stem cells (ESCs) and during differentiation. In order to completely abrogate KDM6 demethylase activity in ESCs we employed a specific inhibitor (GSK-J4, Kruidenier et al. 2012). Treatment of ESCs with GSK-J4 had no effect on viability and proliferation . However, ESC differentiation in the presence of GSK-J4 was completely abrogated. In conclusion we show that ESC differentiation is completely blockend in the absence of any H3K27 demethylase activity. We used microarrays to detail the global gene expression program of genes which are differentially expressed during the early differentiation of ESC derived embryoid bodies (EBs) in the presence of GSK-J4 (KDM6 Inhibitor). ESCs (R1) have been cultured and differentiated in the presence of GSK-J4 a KDM6 specific inhibitor.

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Depletion of demethylase KDM6 enhances early neuroectoderm commitment of human ESCs through inhibiting WNT activation

Project description:Depletion of demethylase KDM6 enhances early neuroectoderm commitment of human ESCs through inhibiting WNT activation

| PRJNA722914 | ENA

A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells

Project description:While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA-binding protein CSDE1 is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post-transcriptional regulator of hESC identity and neurogenesis.

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Project description:Pancreatic cancer remains a deadly disease with limited treatment success. Aberrant epigenetic signaling is increasingly appreciated as a critical driver of tumorigenesis and the potential reversibility of epigenetic underscore their therapeutic potential. Epigenetic factors are often ubiquitous and function in a highly context-dependent manner, necessitating rigorous study of their dynamic and complex roles. We now show that Kdm6 demethylases are critical regulators of pancreatic cancer development and subtype specification and assign a previously unknown oncogenic function to Kdm6b in promoting pancreatic ductal adenocarcinoma (PDA) formation by regulating Notch signaling. Furthermore, activity of both Kdm6a and Kdm6b cooperate to maintain PDA identity and their combined deficiency leads to the rare subtype of sarcomatoid carcinoma. Finally, we demonstrate that pharmacological Kdm6 inhibition by the demethylase inhibitor GSK-J4 shows promise for the development of new pancreatic cancer therapeutic strategies.

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KDM6 Inhibition induces DNA Damage Response (DDR) during ESC Differentiation but not during self-renewal.

2016-03-11 | GSE49886 | GEO

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