Enzymes that catalyze the addition (writers) or removal (erasers) of reversible chemical modifications to DNA and histones. These modifications can be specifically recognized by proteins (readers) that are recruited to regulate downstream chromatin processes. (Image by Alexey Soshnev) 

Enzymes that catalyze the addition (writers) or removal (erasers) of reversible chemical modifications to DNA and histones. These modifications can be specifically recognized by proteins (readers) that are recruited to regulate downstream chromatin processes. (Image by Alexey Soshnev) 

 

Chromatin regulation in normal and cancer development

We are interested in understanding basic mechanisms governing chromatin organization and access during normal and cancer development.

Eukaryotic cells develop sophisticated mechanisms to package and access their genetic information. Recent studies uncover that proteins involved in genome regulation are frequently altered in human developmental syndromes and cancers. These findings agree with laboratory observations that cancer cells often display abnormal nuclear architecture, and raise the questions of whether and how aberrant chromatin landscape facilitates disease development.

Our previous work have largely focused on hotspot, gain-of-function mutations in chromatin modulators and regulators, including IDH1/2 and histone H3, that are frequently identified in a number of adult and pediatric cancer types. Collectively we have delineated the biochemical mechanisms by which these mutations alter global chromatin landscape. We also demonstrated that chromatin mutations are pro-oncogenic through the blockade of cellular differentiation. These findings provide compelling evidence for a causal role of chromatin dysregulation in oncogenesis, and propose a novel pathway of cancer initiation through accumulation of hyper-proliferative and differentiation-refractory tissue progenitor cells driven by epigenome abnormality.

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Building on the conceptual framework that precise chromatin organization is critical for the homeostatic balance between tissue development/repair and tumorigenesis, we aim to use a combination of genetic, (epi)genomic, developmental and cancer biology approaches to dissect molecular connections between chromatin abnormality and (mis)regulation of gene expression in cancer and other human diseases. We believe that by generating a sufficient body of knowledge around the basic mechanisms governing genome regulation, novel paths to epigenetic therapy can be illuminated.