The genomic landscapes of histone H3-Lys9 modifications of gene promoter regions and expression profiles in human bone marrow mesenchymal stem cells

Mesenchymal stem cells （MSCs） of nonembryonic origins possess the proliferation and multi-lineage differentiation potentials. It has been established that epigenetic mechanisms could be critical for determining the fate of stem cells, and MSCs derived from different origins exhibited different expression profiles individually to a certain extent. In this study, ChiP-on-chip was used to generate genome-wide histone H3-Lys9 acetylation and dimethylation profiles at gene promoters in human bone marrow MSCs. We showed that modifications of histone H3-Lys9 at gene promoters correlated well with mRNA expression in human bone marrow MSCs. Functional analysis revealed that many key cellular pathways in human bone marrow MSC self-renewal, such as the canonical signaling pathways, cell cycle pathways and cytokine related pathways may be regulated by H3-Lys9 modifications. These data suggest that gene activation and silencing affected by H3-Lys9 acetylation and dimethylation, respectively, may be essential to the maintenance of human bone marrow MSC self-renewal and multi-potency.

Acetylation of H3K4,H3K9,and H3K27 mediated by p300 regulates the expression of GATA4 in cardiocytes

GATA4 is a particularly important cardiogenic transcription factor and serves as a potent driver of cardiogenesis.Recent progress in the field has made it clear that histone acetylation can influence gene expression through changing the structure of chromatin.Our previous research had revealed that hypo-acetylation could repress gata4 expression in cardiocytes,however the underlying mechanism by which this occurred was still unclear.To reveal the mechanism of histone acetylation involved in the regulation of gata4 transcription,we concentrated on P300,one of the important histone acetyltransferase associated with cardiogenesis.We found that P300 participated in gata4 expression through regulating histone acetylation in embryonic mouse hearts.RNAi-mediated downregulation of P300 modulated the global acetylation of H3 and the acetylation of H3K4,H3K9,and H3K27 in gata4 and Tbx5 promoters.Interestingly,there was an obvious inhibition of gata4 transcription,whereas Tbx5 was not influenced.Furthermore,SGC-CBP30,the selective inhibitor of the bromodomain in CBP/P300,downregulated gata4 transcription by repressing the acetylation of H3K4,H3K9,and H3K27 in the gata4 promoters.Taken together,our results identified that acetylation of H3K4,H3K9,and H3K27 mediated by P300 plays an important role in regulation of gata4 expression in cardiogenesis.

Tongxinluo Reverses the Hypoxia-suppressed Claudin-9 in Cardiac Microvascular Endothelial Cells

Background： Claudin-5, claudin-9, and claudin-11 are expressed in endothelial cells to constitute tight junctions, and their deficiency may lead to hyperpermeability, which is the initiating process and pathological basis of cardiovascular disease.Although tongxinluo （TXL） has satisfactory antianginal effects, whether and how it modulates claudin-5, claudin-9, and claudin-1 1 in hypoxia-stimulated human cardiac microvascular endothelial cells （HCMECs） have not been reported.Methods： In this study, HCMECs were stimulated with CoCl2 to mimic hypoxia and treated with TXL.First, the messenger RNA （mRNA） expression of claudin-5, claudin-9, and claudin-l 1 was confirmed.Then, the protein content and distribution of claudin-9, as well as cell morphological changes were evaluated after TXL treatment.Furthermore, the distribution and content histone H3K9 acetylation （H3K9ac） in the claudin-9 gene promoter, which guarantees transcriptional activation, were examined to explore the underlying mechanism, by which TXL up-regulates claudin-9 in hypoxia-stimulated HCMECs.Results： We found that hypoxia-suppressed claudin-9 gene expression in HCMECs （F=7.244;P =0.011） and the hypoxia-suppressed claudin-9 could be reversed by TXL （F=61.911;P =0.000）, which was verified by its protein content changes （F=29.142;P =0.000）.Moreover, high-dose TXL promoted the cytomembrane localization of claudin-9 in hypoxia-stimulated HCMECs, with attenuation of cell injury.Furthermore, high-dose TXL elevated the hypoxia-inhibited H3K9ac in the claudin-9 gene promoter （F=37.766;P =0.000）, activating claudin-9 transcription.Conclusions： The results manifested that TXL reversed the hypoxia-suppressed claudin-9 by elevating H3K9ac in its gene promoter, playing protective roles in HCMECs.

WHIRLY1 recruits the histone deacetylase HDA15 repressing leaf senescence and flowering in Arabidopsis

Leaf senescence is controlled by a complex regulatory network in which robustness is ensured by the activity of transcription factors and epigenetic regulators.However,how these coordinate the process of leaf senescence remains poorly understood.We found that WHIRLY1 interacts with Histone Deacetylase(HDA)15,a Reduced Potassium Dependence3(RPD3)/HDA1-type HDA,by using green fluorescent protein-nanotrap-mass spectrum assays.The development-dependent interaction between WHIRLY1 and HDA15 was further confirmed by bimolecular fluorescence complementation assays and co-immunoprecipitation assays in Arabidopsis.Multi-omics genome-wide transcriptome and H3K9 acetylome enrichment analysis showed that HDA15 delays leaf senescence and flowering by repressing the expression of the positive regulators of leaf senescence and flowering,such as LOX2 and LARP1 C,and reducing H3K9 ac levels at these loci;WHIRLY1 and HDA15 co-target to the region near the transcription start site of a subset of nutrient recycling-related genes(e.g.,Glutathione S-transferases 10,non-coding RNA,and photosystem II protein D1 synthesizer attenuator PDIL1-2),as well as WRKY53 and ELF4,and co-repress their expression by removing H3K9 acetylation.Our study revealed a key transcription regulatory node of nutrient recycling and senescence-associated genes involved in leaf senescence and flowering via the recruitment of HDA15 by the single-stranded DNA/RNA-binding protein WHIRLY1.