Biology subjects

Distefano-Gagne, F.

Publications and source records attributed to Distefano-Gagne, F..

3 recordsLinked to original sources

bioRxiv2025

Multi-tier signaling and epigenomic reprogramming orchestrate microglial inflammatory states and functions associated with demyelination

The extensive heterogeneity of microglia inflammatory states accompanying neurodegenerative diseases underscores the complex molecular mechanisms that regulate these cells. Here, we report on transcriptional mechanisms that control microglial inflammatory polarization associated with brain demyelination in mice. Using flow cytometry, microscopy and RNA-seq, we identified two dominant, functionally distinct states inflammatory microglia: Clec7a+CD229+CD11c-microglia that are prone to proliferation and that transcribe high levels of extracellular matrix-associated genes, and Clec7a+CD229+CD11c+ microglia characterized by inflammatory tissue-remodeling and antigen presentation gene signatures. Epigenomic analyses implicated genome-wide nucleosome remodeling to the polarization process, driven by state-associated hierarchal stimulation of pro-inflammatory transcription factors, as well as re-calibration of Mef2 homeostatic input. Mechanistically, we confirmed relevance for Trem2, Mef2a and Egr2 to the microglial inflammatory polarization and demyelinating processes. Therefore, distinct configurations of signaling input cooperate with epigenetic mechanisms to reprogram the transcriptional output of microglia to enable their inflammatory functions.

neuroscience↗

bioRxiv2022

Systematic delineation of signaling and epigenomic mechanisms underlying microglia inflammatory activity in acute and chronic brain pathologies

Microglia promptly mount an inflammatory response following detection of infectious agents or injuries in the central nervous system. Such function fundamentally depends upon dynamic modulation of gene expression. However, the signaling and epigenomic mechanisms that regulate the transcriptional process underlying microglial inflammatory activity are not well understood. To address this, we used RNA-seq, ChIP-seq and ATAC-seq to delineate gene signatures and activity across the repertoire of genomic regulatory elements of microglia engaged in acute and chronic neuroinflammatory activity. Systematic interrogations of the microglial population over time during a systemic inflammatory response revealed a coordinated, sequential activation of multiple gene programs associated with defense response, translation and cell cycling. Activation of these programs occurred in parallel with gain and loss of activity at 4,080 and 3,119 genomic cis-regulatory elements, respectively. Furthermore, computational analyses identified key transcriptional regulators, including Ets, AP-1, C/epb, Nf-{kappa}B, Irf, Runx, c-Myc and E2f family members, that display differential propensity for activity at gene promoters and promoter-distal cis-regulatory elements. Gene expression analyses also suggested that the transcriptional process likely contribute to the effective activity of numerous transcriptional regulators through the modulation of their mRNA levels. Finally, characterization of CD11c-positive microglia that emerge with chronic demyelinating brain lesions suggested that Egr2, Mef2 members and E-box-binding factors such as Tfeb and Mitf contribute to the enhanced phagosomal activity of this inflammatory subset. Loss-of-function experiments validated that Mef2a in microglia is necessary for the acquisition of the CD11c-positive phenotype. Collectively, these results demonstrate that the inflammatory activity of microglia arises through an intricate, ultimately context-dependent, interplay between signaling pathways, genomic regulatory elements and the transcriptional machinery.

neuroscience↗

bioRxiv2021

Context-dependent transcriptional regulation of microglial proliferation

Microglia proliferation occurs during brain development and brain lesions, but how this is coordinated at the transcriptional level is not well understood. Here, we investigated transcriptional mechanisms underlying proliferation of mouse microglia during postnatal development and in adults in models of induced microglial depletion-repopulation and brain demyelination. While each proliferative subset displayed globally a distinct signature of gene expression, they also co-expressed a subgroup of 1,370 genes at higher levels than quiescent microglia. Furthermore, expression of these may be coordinated by one of two modes of regulation. A first mode augments expression of genes already expressed in quiescent microglia and is subject to regulation by Klf/Sp, Nfy, and Ets transcription factors. Alternatively, a second mode enables de novo transcription of cell cycle genes and requires additional regulatory input from Lin54 and E2f factors. Overall, proliferating microglia integrate regulation of cell cycle gene expression with their broader, context-dependent, transcriptional landscape.

genomics↗