Biology subjects

Kessler, J.

Publications and source records attributed to Kessler, J..

3 recordsLinked to original sources

bioRxiv2023

New tools to study the interaction between integrins and latent TGFbeta1

Transforming growth factor beta (TGF{beta}) 1 regulates cell differentiation and proliferation in different physiological settings, but is also involved in fibrotic progression and protects tumors from the immune system. Integrin V{beta}6 has been shown to activate latent TGF{beta}1 by applying mechanical forces onto the latency-associated peptide (LAP). While the extracellular binding between V{beta}6 and LAP1 is well characterized, less is known about the cytoplasmic adaptations that enable V{beta}6 to apply such forces. Here, we generated new tools to facilitate the analysis of this interaction. We combined the integrin-binding part of LAP1 with a GFP and the Fc chain of human IgG. This chimeric protein, sLAP1, revealed a mechanical rearrangement of immobilized sLAP1 by V{beta}6 integrin. This unique interaction was not observed between sLAP1 and other integrins. We also analyzed V{beta}6 integrin binding to LAP2 and LAP3 by creating respective sLAPs. Compared to sLAP1, integrin V{beta}6 showed less binding to sLAP3 and no rearrangement. These observations indicate differences in the binding of V{beta}6 to LAP1 and LAP3 that have not been appreciated so far. Finally, V{beta}6-sLAP1 interaction was maintained even at strongly reduced cellular contractility, highlighting the special mechanical connection between V{beta}6 integrin and latent TGF{beta}1.

cell biology↗

bioRxiv2020

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary decidua-derived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how systematic functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

genomics↗

bioRxiv2020

Bone morphogenetic protein 4 reduces global H3K4me3 to inhibit proliferation and promote differentiation of human neural stem cells

Posttranslational modifications (PTMs) on histone tails spatiotemporally dictate mammalian neural stem cell (NSC) fate. Bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor {beta} (TGF-{beta}) superfamily, suppresses NSC proliferation and fosters differentiation into astroglial cells. Whether PTMs mediate these effects of BMP4 is unknown. Here we demonstrate that BMP4 signaling causes a net reduction in cellular histone H3 lysine 4 trimethylation (H3K4me3), an active histone mark at promoters of genes associated with human NSC proliferation. We also show that H3K4me3 reduction by BMP4 is mediated by decreased expression of SETD1A and WDR82, two methyltransferase components of SETD1A-COMPASS. Down-regulation of these components decreases expression of key genes expressed in hNSCs, while ectopic expression via transfection dedifferentiates human astrocytes (HAs). These observations suggest that BMP4 influences NSC fate by regulating PTMs and altering chromatin structure. SIGNIFICANCE STATEMENTBMP4 is critical in determining hNSC fate. Whether histone posttranslational modifications (PTM) mediate the effects of BMP4 is unknown. Here we report that H3K4me3, brought about by its methyltransferases SETD1A and WDR82, at promoters of stem cell genes OCT4 and NESTIN is involved in human neural stem cell (hNSC) maintenance. BMP4 promotes hNSC astroglial differentiation in part through reduction of SETD1A and WDR82 and thus decreased frequency of H3K4me3 at the promoters of these genes. These results provide evidence that BMP4 promotes hNSC differentiation through a potential epigenetic mechanism and extend our understanding of the role of histone PTM in central nervous system development.

neuroscience↗