Research Summary

Functional characterization of human DBC1 complex in eukaryotic transcriptional regulation and leukemic transformation

Our lab is primarily interested in mechanistic understanding of eukaryotic transcriptional regulation. Over last several years, epigenetic regulation has been shown to have major roles in eukaryotic transcription and associated diseases.

Epigenetic histone methylation at H3-Lysine 4 (H3-K4) by human MLL (Mixed Lineage Leukemia) proteins play important roles in transcriptional activation of key developmentally regulated HOX genes during hematopoietic differentiation. Among the described MLL proteins (MLL1-5), our research interest is focused on transcriptional regulatory mechanisms involving MLL1 (hereafter MLL).

Balanced chromosomal translocation between MLL and variety of other fusion partners (>80) result in MLL fusion proteins, that in conjunction with wild type MLL, give rise to various acute lymphoid and myeloid leukemia (ALL and AML). Majority of these fusion partners (AF9, AFF1, ELL, ENL, AF10 etc.) have been shown to have roles in regulating transcriptional elongation. However, their precise regulatory mechanisms are not clearly understood.

With an aim of mechanistic understanding of transcriptional regulation by MLL fusion partner proteins and thereby MLL fusion proteins, our initial studies have shown that these factors form various distinct protein complexes with overlapping subunits (see figure below). Formation of these complexes may have implication in dynamic regulation of different stages of transcription elongation.

Currently, we are focusing our studies on novel interacting partners of the MLL fusion partner proteins that we propose to have important roles in regulating transcription elongation and disease pathogenesis. We would employ various biochemical and cell biological approaches for detailed mechanistic understanding of their mechanisms of action. Finally, we aim to use mouse model for validating the role of these mechanistic understanding in disease pathogenesis by respective MLL fusion proteins.

Figure Legend: Cartoon diagram depicting distinct protein complex formation with overlapping subunits by common MLL fusion partners and other important transcriptional regulatory proteins