Allison Cheney
Allison Cheney is a Ph.D. candidate at the University of California Santa Cruz in the department of Molecular, Cell, and Developmental Biology. She is currently working in the lab of Dr. Olena Vaske and is studying the developmental origins of pediatric brain tumors using single cell data.
Abstract
Allison Cheney, Yuanqing (Bianca) Xue, A. Geoffrey Lyle, Ellen T. Kephart, Josh M. Stuart, Olena M. Vaske
University of California, Santa Cruz, Santa Cruz, CA, United States
H3K27-altered diffuse midline gliomas (DMGs) are devastating cancers occurring mainly in young children in the thalamus and brainstem, characterized by a mutation which inhibits the polycomb repressive complex 2 (PRC2) and the resultant widespread loss of the repressive histone modification H3K27me3. H3K27me3 is essential for lineage differentiation. We assembled a single cell dataset from the normal human prenatal and young adult thalamus to better understand the precise regional and developmental origins of these thalamic tumors. Previous studies have been limited by the lack of human data in the thalamus. We annotated DMG and normal cells by cell type (including neural progenitor cells (NPCs), oligodendrocyte progenitor cells (OPCs), oligodendrocytes, and astrocytes) and compared gene expression of DMG cells to their matched normal cell type. In glioma NPCs and OPCs, a significant increase was found in many members of both the canonical and variant PRC1 complexes which deposit the repressive H2AK119 ubiquitination mark as well as members of the polycomb repressive de-ubiquitinase complex including the catalytic subunit BAP1.
Additionally, members of the SRCAP/EP400 complex, which exchange the canonical histone H2A for H2A.Z, were shown to be upregulated in DMG NPCS. Consistently, H2A.Z targets were found to be upregulated in DMG NPCs.
H2A.Z has been shown to facilitate the deposition of H3K27me3 at bivalent promoters and promote neuronal and glial differentiation.
Together, our data point to widespread chromatin reprogramming and remodeling beyond loss of H3K27me3 in DMG NPCs and OPCs, perhaps as a compensatory mechanism to allow for glial lineage differentiation.