Biology subjects

Lei, I.

Publications and source records attributed to Lei, I..

3 recordsLinked to original sources

bioRxiv2019

Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via mediating histone acetylation

Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA significantly improved heart function in I/R rats by administration of sodium octanoate (8C). Mechanistically, 8C prevented I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes HO1, NQO1 and SOD2 and inhibited cardiomyocyte apoptosis. Furthermore, we identified that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a. Therefore, our results demonstrate that 8C dramatically improves cardiac function through metabolic acetyl-CoA-mediated histone acetylation. This study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a in stimulating histone acetylation and anti-oxidative stress gene expression to combat heart injury.

cell biology↗

bioRxiv2019

SWI/SNF component BAF250a coordinates OCT4 and WNT signaling pathway to control cardiac lineage differentiation

Dissecting epigenetic mechanisms controlling early cardiac differentiation will provide insights into heart regeneration and heart disease treatment. SWI/SNF complexes remodel nucleosomes to regulate gene expression and play a key role in organogenesis. Here we reported a unique function of BAF250a in regulating the physical interaction of OCT4 and {beta}-CATENIN during cardiac lineage differentiation from human ESCs. BAF250a deletion greatly reduced the physical interaction between OCT4 and {beta}-CATENIN but did not alter the expression of {beta}-CATENIN and OCT4 in the mesodermal progenitor cells. BAF250a ablation led to decreased recruitment of OCT4 and {beta}-CATENIN at promoters of key mesodermal lineage genes, such as MESP1 and EOMES. Subsequently, the expression of lineage specific genes was down-regulated whereas the expression of pluripotent genes was up-regulated. In parallel, BAF250a ablation also altered recruitments of OCT4 and {beta}-CATENIN to the promoter of CCND2 and CCND3, two key genes for S phase entry during cell cycle. Consequently, BAF250a deletion led to prolonged S phase in Mesp1+ cardiac progenitor cells, which in turn inhibited efficient differentiation of Mesp1+ to Isl1+ cells. Furthermore, BAF250a deletion abolished the interaction of OCT4 and BRG1 in mesoderm, suggesting that BAF250a is the key component in SWI/SNF complex that determines the interaction of Oct4/{beta}-catenin in mesoderm. In contrast, we found that BAF250a did not regulate the OCT4/{beta}-CATENIN interaction during neuroectoderm differentiation. Altogether, our results suggest that BAF250a specifically controls proper cardiac mesoderm differentiation by reorganizing the binding of OCT4/{beta}-CATENIN and regulates both key lineage differentiation genes and cell cycle genes coincided in response to WNT/{beta}-CATENIN signal.\n\nHighlightsBAF250a is required for hESC cardiac differentiation\n\nBAF250a is required for the assembly of Brg1/OCT4/{beta}-CATENIN complex and the recruitment of OCT4/{beta}-CATENIN to cardiac genes\n\nBAF250a is dispensable for the interaction of OCT4/{beta}-CATENIN interaction in neuroectoderm differentiation\n\nBAF250a interacts with OCT4/{beta}-CATENIN to promote cardiac differentiation by regulating cell cycle.

developmental biology↗

bioRxiv2019

Enhancing Cardiac Reprogramming by Suppressing Specific C-C Chemokine Signaling Pathways

Reprogramming fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for heart regeneration. Yet a major challenge is the low conversion rate. To address this challenge, we screened and identified four chemicals, insulin-like growth factor-1, Mll1 inhibitor MM589, transforming growth factor-{beta} inhibitor A83-01, and Bmi1 inhibitor PTC-209, termed as IMAP, that coordinately enhanced reprogramming efficiency.\n\nUsing -muscle heavy chain -green fluorescent protein mouse embryo fibroblasts as the staring cell type, we observed a six-fold increase of iCM formation with IMAP treatment. IMAP stimulated higher cardiac troponin T and -actinin expression and more sarcomere formation with up-regulation of many cardiac genes and down-regulation of fibroblast genes. Furthermore, IMAP promoted higher spontaneous beating and calcium transient activities of iCMs derived from neonatal cardiac fibroblasts. Intriguingly, we identified that many genes involved in immune responses, particularly those in specific C-C chemokine signaling pathways, were repressed with IMAP treatment. We next tested C-C chemokine ligands Ccl3, Ccl6, and Ccl17 in cardiac reprogramming and observed inhibitory effect on iCM formation, while corresponding inhibitors of Ccr1, Ccr4, and Ccr5 had the opposite effect. These results indicated that suppression of specific C-C chemokine signaling pathways was a direct down-stream event of IMAP treatment that enhanced cardiac reprogramming.\n\nIn conclusion, we identified a combination of four chemicals IMAP in suppressing specific C-C chemokine signaling pathways and facilitating MGT-induced cardiac reprogramming. Our studies revealed the role of these specific C-C chemokine signaling pathways in cardiac reprogramming and provide potential targets in iCM formation and its clinical applications.

cell biology↗