Biology subjects

Sinha, T.

Publications and source records attributed to Sinha, T..

3 recordsLinked to original sources

bioRxiv2021

ETV2 primes hematoendothelial gene enhancers prior to hematoendothelial fate commitment

The lineage-determining transcription factor ETV2 is necessary and sufficient for hematoendothelial fate commitment. We investigated how ETV2-driven gene regulatory networks promote hematoendothelial fate commitment. We resolved the sequential determination steps of hematoendothelial versus cardiac differentiation from mouse embryonic stem cells. Etv2 was strongly induced and bound to the enhancers of hematoendothelial genes in a common cardiomyocyte-hematoendothelial mesoderm progenitor. However, only Etv2 itself and Tal1, not other ETV2-bound genes, were induced. Despite ETV2 genomic binding and Etv2 and Tal1 expression, cardiomyogenic fate potential was maintained. A second wave of ETV2-bound target genes was up-regulated during the transition from the common cardiomyocyte-hematoendothelial progenitor to the committed hematoendothelial population. A third wave of ETV-bound genes were subsequently expressed in the committed hematoendothelial population for sub-lineage differentiation. The shift from ETV2 binding to productive transcription, not ETV2 binding to target gene enhancers, drove hematoendothelial fate commitment. This work identifies mechanistic phases of ETV2-dependent gene expression that distinguish hematoendothelial specification, commitment, and differentiation. HIGHLIGHTSO_LIThe hematoendothelial master TF ETV2 is expressed in a multipotent mesoderm progenitor. C_LIO_LIETV2 binds to target genes in the mesoderm progenitor without target gene activation. C_LIO_LIETV2 binding in the mesoderm progenitor does not diminish alternative cardiac fate potential. C_LIO_LIETV2-bound target genes are activated upon hematoendothelial fate commitment. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/449981v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@371c3dorg.highwire.dtl.DTLVardef@1ee8e7org.highwire.dtl.DTLVardef@14ca731org.highwire.dtl.DTLVardef@1748ff7_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2020

Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

Host genetics are known to influence the gut microbiome, yet their role remains poorly understood. To robustly characterize these effects, we performed a genome-wide association study of 207 taxa and 205 pathways representing microbial composition and function within the Dutch Microbiome Project, a population cohort of 7,738 individuals from the northern Netherlands. Two robust, study-wide significant (p<1.89x10-10) signals near the LCT and ABO genes were found to affect multiple microbial taxa and pathways, and were replicated in two independent cohorts. The LCT locus associations were modulated by lactose intake, while those at ABO reflected participant secretor status determined by FUT2 genotype. Eighteen other loci showed suggestive evidence (p<5x10-8) of association with microbial taxa and pathways. At a more lenient threshold, the number of loci identified strongly correlated with trait heritability, suggesting that much larger sample sizes are needed to elucidate the remaining effects of host genetics on the gut microbiome.

genetics↗

bioRxiv2020

The Dutch Microbiome Project defines factors that shape the healthy gut microbiome

The gut microbiome is associated with diverse diseases, but the universal signature of an (un)healthy microbiome remains elusive and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. To fill this gap, we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We then correlated this to 241 host and environmental factors, including physical and mental health, medication use, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is primarily shaped by environment and cohousing. Only [~]13% of taxa are heritable, which are enriched with highly prevalent and health-associated bacteria. By identifying 2,856 associations between microbiome and health, we find that seemingly unrelated diseases share a common signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, of which numerous early-life and current factors are particularly linked to the microbiome. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.

microbiology↗