Research Interests
Control of B and T cell Development and Epigenetic Mechanisms.
Key words: Transcription, Epigenetics, Lineage Development, Long distance DNA interactions.
Research Description
The Atchison laboratory studies the molecular mechanisms responsible for transcriptional regulation, epigenetic processes, and the control of B and T cell lineage development.
Much of our work currently focuses on the function of transcription factor YY1 in controlling hematopoietic lineage commitment via long-range chromatin interactions coupled with repressive histone modifications. Interestingly, conditional knockout of YY1 in the B cell lineage enables YY1-null pro-B cells to develop into the T cell lineage both in vitro and in vivo. In addition, we found YY1-null pro-B cells are able to dedifferentiate into hematopoietic precursor cells, and to differentiate into numerous alternative lineages. Our studies may define a universal mechanism for lineage commitment that may be manipulated both experimentally, as well as therapeutically.
Key questions being addressed include:
1. What is the mechanism of B lineage commitment? We hypothesize that YY1 is recruited early in lineage development to key locations in the genome by action of pioneer transcription factors. YY1 subsequently forms and stabilizes long distance DNA interactions at lineage-appropriate genes, and recruits the Polycomb Group complex to generate H2K27me3 modifications at alternative lineage genes. We hypothesize these two processes stabilize lineage commitment.
2. What is the mechanism of YY1 control of chromatin structures that regulate commitment? We are testing in vitro and in vivo key YY1 mutants that ablate specific YY1 functions such as transcriptional activation, Polycomb recruitment, self-association, and DNA binding, for their impact on chromatin structure, long-distance DNA interactions, and immunoglobulin locus contraction needed for V(D)J rearrangement.
3. What is the breadth of hematopoietic plasticity caused by YY1 knockout? Using lineage-specific CRE drivers and a Rosa26-Cherry readout, we are determining the numerous hematopoietic lineages that can develop from YY1-null pro-B cells. These studies are showing unusual levels of lineage plasticity caused by YY1 knock-out.
4. What are the molecular and functional fidelities of alternative lineage cells that develop from YY1-null pro-B cells? Using Hi-C, ChIP-seq, ATAC-seq, RNA-seq, and proteomic approaches we are determining the molecular fidelity of T lineage cells that develop from YY1-null pro-B cells. These molecular studies are being complemented with cellular assays to measure T cell functions.
5. Are T lineage cells equally developmentally plastic after YY1 knockout? As we hypothesize that the mechanism we have identified is commonly used in lineage commitment, we anticipate that other hematopoietic lineages will be developmentally plastic after YY1 knockout.
Lab personnel:
Michael Atchison, Ph.D. P.I.
Frank Wilkinson, Ph.D. Visiting Scientist
Arindam Basu, Ph.D. Visiting Scientist
Suchita Hodawadekar, M.S. Research Specialist
Sarmistha Banerjee, Ph.D. Research Associate