Research Projects

Analysis of MLL family of proteins in leukaemias

CRG — Centre for Genomic Regulation

Barcelona

Spain

2/13

Supervision

Luciano Di Croce
CRG, 1st Supervisor

Genevieve Almouzni
Institut Curie, 2nd Supervisor

Objectives

Understand how the misexpression of MLL proteins is implicated in leukemogenesis.

Methodology

Epigenetic regulation of gene expression is one of the key mechanisms regulating cell-fate choices and cell identity during development. One of the most prominent and enigmatic epigenetic regulatory systems involves the evolutionarily conserved Polycomb group (PcG) and Trithorax group (TrxG) components, acting antagonistically to orchestrate the expression of key genes in cell differentiation and developmental processes.
TrxG is a heterogeneous group that plays a widespread role in transcriptional activation, including the SWI/SNF complex and MLL family. The histone methyltransferase complex MLL was first isolated in yeast and is well conserved across all pre-metazoan and major animal lineages. MLL complexes catalyse the deposition of methyl group on lysine 4 of histone H3.
Functional diversity of the modification of H3K4 by the MLL family in metazoans has been demonstrated through biochemical and high throughput-based genomic studies. MLL proteins are often mutated, deleted, truncated and translocated in several human pathologies, including leukemias. ESR2 will study the role of MLL family members in leukemogenesis using both hematopoietic stem cells as well as patient-derived leukemic cells.

Expected Results

Revealing the role of MLL complexes in altering hematopoietic stem cells functions. Identifying a novel target to treat leukaemias.

Planned Secondments

IEO, Italy (3 months):
Performing knockdown or CRISPR deletion in a human leukemic cell.
Diagenode, Belgium (2 months):
Performing low-number of cell ChIP-seq analysis.
Chromatin accessibility assays.

Enrolment in doctoral programs

PhD in Biochemistry from Universitat Pompeu Fabra, Barcelona

References

Hu, D. et al. Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification. Mol Cell 65, 460-475 e466, doi:10.1016/j.molcel.2017.01.013 (2017).

Morey, L., Santanach, A. & Di Croce, L. Pluripotency and Epigenetic Factors in Mouse Embryonic Stem Cell Fate Regulation. Mol Cell Biol 35, 2716-2728, doi:10.1128/MCB.00266-15 (2015).