H3K18ac Primes Mesendodermal Differentiation upon Nodal Signaling

Abstract

SummaryCellular responses to transforming growth factor β (TGF-β) depend on cell context. Here, we explored how TGF-β/nodal signaling crosstalks with the epigenome to promote mesendodermal differentiation. We find that expression of a group of mesendodermal genes depends on both TRIM33 and nodal signaling in embryoid bodies (EBs) but not in embryonic stem cells (ESCs). Only in EBs, TRIM33 binds these genes in the presence of expanded H3K18ac marks. Furthermore, the H3K18ac landscape at mesendodermal genes promotes TRIM33 recruitment. We reveal that HDAC1 binds to active gene promoters and interferes with TRIM33 recruitment to mesendodermal gene promoters. However, the TRIM33-interacting protein p300 deposits H3K18ac and further enhances TRIM33 recruitment. ATAC-seq data demonstrate that TRIM33 primes mesendodermal genes for activation by maintaining chromatin accessibility at their regulatory regions. Altogether, our study suggests that HDAC1 and p300 are key factors linking the epigenome through TRIM33 to the cell context-dependent nodal response during mesendodermal differentiation.

A Nodal enhanced micropeptide NEMEP regulates glucose uptake during mesendoderm differentiation of embryonic stem cells

“…1f, g ). We also found that TRIM33— a Nodal signaling-specific chromatin reader that associates with H3K9me3 and H3K18ac dual marks to regulate the expression of mesendoderm LDTFs 21 , 25 —is essential for Gm11549 induction during mesendoderm differentiation and Gm11549 transcription was not induced by Nodal/Activin stimulation in Trim33 null cells (Fig. 1g , and Supplementary Fig.…”

“…We analyzed the ChIP-seq data (TRIM33, SMAD2/3, SMAD4, FOXH1) as previously described 21 , 44 . Briefly, the data were trimmed using TrimGalore (version 0.6.1) and then aligned to mm10 using Bowtie2 (version 2.3.3).…”

“…These proteins mediate their multifunctional effects in cells by eliciting transcriptional responses on many target genes, specifically through the receptor-activated SMADs (R-SMADs). R-SMADs—SMAD2 and SMAD3 for TGFβ, Nodal, Activin, and myostatin signaling—translate TGF-β pathway signals into the specific transcriptional programs in specific cell contexts, doing so via their interactions with SMAD4 and other transcriptional activators, coactivators/corepressors, and/or epigenetic regulators at enhancer elements in specific genes 16 – 21 . Nodal signaling initiates gastrulation in vivo and promotes embryonic stem cells (ESCs) to differentiate towards mesendoderm fates in vitro; these regulatory processes are mediated by the transcriptional upregulation of so-called “mesendoderm lineage determining transcription factors” (LDTFs) 22 – 24 .…”

A Dynamic and Combinatorial Histone Code Drives Malaria Parasite Asexual and Sexual Development

“…AP2-G2 is associated with H3K18ac and H3K23ac and interacts with ISWI, which has a relatively high homology to TRIM24 (42% identity), which is a reader of H3K18ac and H3K23ac ( 106 , 107 ). Furthermore, the writers of H3K18ac and H3K23ac, p300/CBP activator ( 108 , 109 , 110 ), have homology to the P. falciparum histone acetyltransferase, GCN5 (PF3D7_0823300, 34% identity). Furthermore, TRIM24 has been described as CBP-associated proteins ( 111 ).…”

A dynamic and combinatorial histone code drives malaria parasite asexual and sexual development

“…AP2-G2 additionally interacts with other chromatin regulation proteins, including a chromatin assembly factor 1 subunit A (PF3D7_0501800, CAF1A) and a ISWI chromatin-remodelling complex ATPase (PF3D7_0624600, ISWI), which interacts with a Snf2-related CBP activator (PF3D7_0820000). Both ISWI and Snf2/CBP are homologues of the mammalian H3K18acK23ac writer and reader, p300 and TRIM24, respectively (Halasa et al ., 2019; Luo et al ., 2019; Lv et al ., 2017; Ma et al ., 2016; Tsai et al ., 2010). This suggest that the SAGA-like complex of P. falciparum has as core GCN5/ADA2/PHD2 but in gametocytes, association with the H3K18acK23ac combination includes the additional ISWI/SNF complex effectors.…”