Biology subjects

Jhala, U. S.

Publications and source records attributed to Jhala, U. S..

3 recordsLinked to original sources

bioRxiv2022

TRB3 augments IL1β-TLR4 signaling by engaging Flightless-homolog 1.

Signaling via IL1{beta} and TLR4 receptors (IL1R-TLR4) plays a crucial role in cytokine and fatty acid-induced beta cell inflammation, in type 1 and type 2 diabetes respectively. IL1R-TLR4 share signaling mechanisms via a common, cytoplasmic, toll-like-receptor domain to activate proinflammatory JNK and IKK kinases. We have previously reported that in response to IL1{beta}, pancreatic islets isolated from TRB3 knockout (TRB3KO) mice show attenuated kinetics of activation for MAP3K MLK3, and JNK stress kinases. Here we report that similar to MLK3 and JNK, TRB3KO islets also show a decrease in amplitude and duration of IL1{beta}/LPS-stimulated TAK1 and IKK phosphorylation. Thus, loss of TRB3 attenuates both pathways critically required for a full-blown, cytokine-inducible, proapoptotic response in beta cells. TRB3KO islets display a sharp decrease in cytokine-induced beta cell death, accompanied by a decrease in select downstream NFkB targets, most notably, inducible Nitric Oxide Synthase (iNOS/NOS2), a well-characterized mediator of beta cell dysfunction and death. In order to better understand the molecular basis of TRB3-enhanced IL1R-TLR4 signaling, we interrogated the TRB3 interactome and identified Flightless-homolog 1 (Fli1), an immunomodulatory, actin-binding, leucine-rich-repeat protein, as a novel TRB3-interaction factor. TRB3 binds and disrupts Fli1-dependent sequestration of MyD88, thereby increasing availability of this proximal adaptor to participate in IL1R-TLR4 signaling. Fli1 forms a multiprotein complex that can disconnect IL1R-TLR4 from MyD88, resulting in a brake on assembly of downstream signaling complexes. By interacting with Fli1, TRB3 lifts the brake on IL1R-TLR4 signaling to augment the proinflammatory response in beta cells.

biochemistry↗

bioRxiv2019

Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Adaptation of the islet {beta}-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in {beta}-cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurs at sites occupied by the chromatin-modifying enzyme Lsd1 in islets. We demonstrate that {beta}-cell-specific deletion of Lsd1 leads to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited similar epigenetic and transcriptional changes. Moreover, genetic variants associated with fasting glucose and type 2 diabetes are enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined. Our findings reveal that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.

physiology↗

bioRxiv2019

LSD1-mediated enhancer silencing enables endocrine cell development through attenuation of retinoic acid signalling.

Developmental progression depends on temporally defined changes in gene expression mediated by transient exposure of lineage intermediates to signals in the progenitor niche. To identify a possible contribution of cell-intrinsic epigenetic mechanisms to signal-induced transcriptional responses, we manipulated the signalling environment and activity of the histone demethylase LSD1 during stepwise differentiation of gut tube intermediates into pancreatic endocrine cells. Analysis of enhancer and transcriptome landscapes revealed that lineage progression and endocrine cell differentiation requires LSD1-mediated silencing of transiently active retinoic acid (RA)-induced enhancers. In the absence of LSD1, early RA-responsive enhancers remain partially active despite RA removal, resulting in perduring expression of RA-induced genes, and failure to progress in development. Our findings identify LSD1-mediated enhancer silencing as a cell-intrinsic epigenetic feedback mechanism by which the duration of the transcriptional response to a developmental signal is limited. Given LSD1s requirement in numerous developmental contexts, the here-described mechanism would be broadly relevant.

developmental biology↗