Morc3: A new master regulator in early B and T cell development

Summary

Many of the epigenetic factors critical for the precisely coordinated development of immune cells have yet to be elucidated. Readers, Writers, or Erasers of chromatin marks are intriguing candidates to fulfil roles as master regulators of immune function and development. We identified the H3K4me3 reader Morc3 from a mutagenesis screen for modifiers of epigenetic reprogramming in the mouse. Our preliminary data suggest that Morc3 is a crucial, but thus far unrecognized epigenetic factor in immune cell development. Morc3 disruption results in a multi-lineage phenotype in homozygous mutant embryos. We hypothesize that Morc3 disrupts transcriptional and chromatin processes necessary for lineage specification and commitment. The central premise of this application is to elucidate at which stages and how, Morc3 participates in the molecular events necessary for T and B cell development. We further aim to unravel how it is functionally connected to key lineage factors of lymphopoiesis. By combining state of the art flow cytometry, genetics, epigenomics, and in vivo reconstitution studies, we expect this study to uncover, for the first time, a key role for Morc3 in immune function, and to provide mechanistic insight how Morc3 interacts with known lineage factors to reach a particular immune cell state. Novel fundamental insights into the role of chromatin in cell lineage decisions, into the consequences of disruptions to these processes on gene expression programs and immune cell development will be generated. This will increase our understanding of the transcriptional and epigenetic networks orchestrating immune cell development and function, and how they can be influenced.

Details

Project number

ALWOP.358

Main applicant

Dr. L. Clemens-Daxinger

Affiliated with

Universiteit Leiden, Leids Universitair Medisch Centrum, Divisie 4

Team members

VDC Della Chiara

Duration

01/06/2018 to 31/12/2021

Budget

EUR259,474