Microglia and Fn14 regulate transcription and chromatin accessibility in developing neurons

Ferro, Austin, Vrudhula, Uma, Auguste, Yohan SS, Cheadle, Lucas (August 2021) Microglia and Fn14 regulate transcription and chromatin accessibility in developing neurons. bioRxiv. ISSN 2692-8205 (Submitted)

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Abstract

Cytokine signaling pathways that promote inflammation in peripheral tissues are repurposed to coordinate the refinement of synaptic connections in the developing brain. However, the downstream mechanisms through which these pathways mediate neural circuit maturation remain to be fully defined. Here, we demonstrate that Fn14, a cytokine receptor that promotes inflammation outside of the central nervous system, shapes the transcriptional profiles and chromatin landscapes of neurons in the developing brain. Single-nucleus RNA-sequencing revealed hundreds of misregulated genes in the thalamocortical neurons of the visual thalami of mice lacking either Fn14 or its microglial derived cytokine ligand TWEAK, including genes encoding proteins with critical roles in synaptic function, histone modification, and chromatin remodeling. Whole-genome analysis uncovered significant alterations in chromatin accessibility in the brains of mice lacking Fn14 or in wild-type mice following microglial depletion, and chromatin changes due to both manipulations were enriched near genes encoding regulators of synaptic function. Loss of microglia also led to the retention of excess synapses, suggesting that microglia may link modifications in neuronal chromatin to the functional refinement of neural circuits. Consistent with Fn14 shaping brain function beyond the visual system, Fn14 knockout mice displayed impairments in memory task proficiency as well as heightened sensitivity to pharmacologically induced seizures. Taken together, these results define a previously undescribed interaction between microglia, cytokine signaling, and the neuronal epigenome that is likely to contribute to neural circuit refinement and function in the brain.

Item Type:	Paper
Subjects:	organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > microglia organs, tissues, organelles, cell types and functions > cell types and functions > cell types > microglia organs, tissues, organelles, cell types and functions > cell types and functions > cell types > microglia organs, tissues, organelles, cell types and functions
CSHL Authors:	Ferro, Austin Auguste, Yohan Cheadle, Lucas Vrudhula, Uma
Communities:	CSHL labs > Lippman lab CSHL labs > Cheadle lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	16 August 2021
Date Deposited:	08 Apr 2026 13:29
Last Modified:	08 Apr 2026 13:29
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42148

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