Poster abstracts

Poster number 12 submitted by Rajbir Singh

Histone variants:from epigenetic regulation to cancer screening

Rajbir Singh (Molecular and Cellular Biochemistry), Xiaodan Su (OSU), David Lucas (OSU), Melanie Davis (OSU), Michael Freitas (MVIGM, OSU), John Byrd (Hematology and Oncology, OSU)

Abstract:

Epigenetic regulation comprises the changes in gene expression that are not mediated at the DNA sequence level. Molecular mechanisms that mediate epigenetic regulation mainly include DNA methylation and chromatin modifications. Emerging evidence indicates that both mechanisms act in concert to provide stable and heritable gene expression patterns in higher eukaryotic genomes. Since epigenetic alterations are recognized to occur in various developmental disorders and cancer, understanding this intrinsic complexity of chromatin structure is critical in understanding and treating these diseases. In our study, we have uncovered a new level of complexity in human chromatin due to the presence of functionally distinct isoforms of the replication-dependent core histones that can influence cell proliferation and tumorigenicity. In our effort to understand the epigenetic changes associated with the leukemic state, the histone pool from B-cells of Chronic Lymphocytic Leukemia (CLL) patients was isolated and the mass spectrometry analysis was carried out to map the entire spectrum of changes involved in the malignant state. The most significant change associated with CLL was the relative decrease in abundance of specific replication-dependent histone H2A isoforms. In addition to alterations in the levels of H2A variants at the protein level, changes in H2A isoform mRNA abundance were also observed in many CLL patients. We extended the scope of our study to other cancers and observed a relative decrease in H2A isoform abundance in bladder and breast cancers as well. Though these isoforms differ by just 1-2 residues from their canonical counterparts, siRNA-mediated knockdown studies revealed that these are functionally distinct. In particular, knockdown of specific isoforms can alter the rate of cell proliferation and stimulate anchorage-independent growth. Therefore, further studies will provide novel insights into both the complexity of chromatin and cancer biology.

Keywords: histone variants, cancer