Biology subjects

Gomez-Salinero, J. M.

Publications and source records attributed to Gomez-Salinero, J. M..

4 recordsLinked to original sources

bioRxiv2025

Loss of the alternative calcineurin variant CnAβ1 enhances brown adipocyte differentiation and drives metabolic overactivation through FoxO1 activation

The alternative calcineurin A variant CnA{beta}1 has a unique C-terminal domain that provides it with distinct subcellular localization and mechanism of action different from other calcineurin isoforms. Here, we used mice lacking CnA{beta}1s C-terminal domain (CnA{beta}1{Delta}i12) to show that the absence of this specific isoform strongly reprograms metabolism. CnA{beta}1{Delta}i12 mice on a high-fat diet showed reduced body weight, white adipose tissue (WAT) mass, and circulating triglycerides, together with enhanced insulin sensitivity. In brown adipose tissue (BAT), CnA{beta}1 deficiency increased mitochondrial content and upregulated fatty acid oxidation and thermogenic proteins, improving cold resistance. Conversely, under starvation, CnA{beta}1{Delta}i12 mice experienced rapid fat depletion and hypothermia. Importantly, BAT-specific FoxO1 knockout in CnA{beta}1{Delta}i12 mice reduced catabolism-related gene expression and partially reversed the metabolic phenotypes, increasing body weight and WAT mass. Our findings reveal a relevant role for CnA{beta}1 in orchestrating BAT metabolism, highlighting its potential as a therapeutic target for obesity and metabolic syndrome.

physiology↗

bioRxiv2023

Transcriptional Activation of Regenerative Hematopoiesis via Vascular Niche Sensing

Transition between activation and quiescence programs in hematopoietic stem and progenitor cells (HSC/HSPCs) is perceived to be governed intrinsically and by microenvironmental co-adaptation. However, HSC programs dictating both transition and adaptability, remain poorly defined. Single cell multiome analysis divulging differential transcriptional activity between distinct HSPC states, indicated for the exclusive absence of Fli-1 motif from quiescent HSCs. We reveal that Fli-1 activity is essential for HSCs during regenerative hematopoiesis. Fli-1 directs activation programs while manipulating cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche. During regenerative conditions, Fli-1 presets and enables propagation of niche-derived Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional HSC impairments in the absence of Fli-1. Applying FLI-1 modified-mRNA transduction into lethargic adult human mobilized HSPCs, enables their vigorous niche-mediated expansion along with superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immune regenerative medicine.

cell biology↗

bioRxiv2022

A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin

Plasticity between cell lineages is a fundamental but poorly understood property of regenerative tissues. In the gut tube, small intestine absorbs nutrients whereas colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screen, we identified MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrain colonic plasticity. MTA2 loss in adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-binds with HNF4A, an activating pan-intestine transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic and gain on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through a HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages; their release unleashes plasticity.

developmental biology↗

bioRxiv2021

Transcription factor induction of vascular blood stem cell niches in vivo

The hematopoietic niche is a supportive microenvironment comprised of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses, we define a conserved gene expression signature and cis-regulatory landscape unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code involving members of the Ets, Sox and Nuclear Hormone Receptor families that is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.

developmental biology↗