Myogenic cell identity regulation by H3.3 histone chaperones HIRA and DAXX – MyoID

Skeletal muscle homeostasis and repair after injury mainly relies on muscle stem cells (satellite cells), which are able to self-renew and differentiate into new muscle fibres. Undifferentiated satellite cells express the paired homeobox transcription factor PAX7 and upon muscle injury, they become activated and induce the expression of lineage-specific transcription factors required for myogenic commitment, such as MYOD. The H3.3 histone chaperone HIRA, has been shown to be required for the normal and timely expression of Myod1 in satellite cell activation and myoblast differentiation. Moreover, HIRA is required to sustain myogenic cell identity by promoting myogenic gene expression and inhibiting the expression of alternative lineage genes. Our project aims to identify if a cell fate transition is present at the single cell level in satellite cells lacking HIRA, and if the cellular identity regulation by HIRA-H3.3 axis is conserved in other cell lineages. Moreover, we plan to investigate if the H3.3 histone chaperone function of DAXX is implicated in transcriptional regulation and cell identity. To develop this project, we will use inducible mouse lines to delete Hira and Daxx in vivo and we will perform genome-wide transcriptomic and epigenomic studies combined to bioinformatics analysis. Taken together, we will investigate whether DAXX-H3.3 and HIRA-H3.3 axis share functional similarities and if compensatory mechanisms are at play to regulate cell identity via de incorporation of H3.3 in the genome.