The epigenetic reader MORC3 is required for T cell development in the thymus

Cell fate decisions are orchestrated by an interplay of epigenetic factors in collaboration with transcriptional activators and repressors. The epigenetic reader MORC3 is known as a silencer of endogenous retroviruses in mouse embryonic stem cells. Here, we show that mouse MORC3 is expressed in the thymus and reveal that MORC3 loss of function leads to a severe arrest in T cell development at the DN1 stage, accompanied by an expansion of natural killer and myeloid cells. MORC3 function in thymus depends on its ATPase and its ability to bind H3K4me via the CW-type zinc finger domain. We find altered chromatin accessibility at regulatory elements of key T cell transcription factors in DN1 cells and show that re-expressing TCF1 in MORC3-deficient progenitor cells, rescues T cell development. Our work indicates a novel function for MORC3 in modulating regulatory sites essential for T cell lineage commitment at the level of chromatin.