Faculty Collaboration Database

Discovery, expression, cellular localization, and molecular properties of a novel, alternative spliced HP1γ isoform, lacking the chromoshadow domain. PLoS One 2020;15(2):e0217452

Date

02/07/2020

Pubmed ID

32027651

Pubmed Central ID

PMC7004349

DOI

10.1371/journal.pone.0217452

Scopus ID

2-s2.0-85079081692 (requires institutional sign-in at Scopus site)   4 Citations

Abstract

By reading the H3K9Me3 mark through their N-terminal chromodomain (CD), HP1 proteins play a significant role in cancer-associated processes, including cell proliferation, differentiation, chromosomal stability, and DNA repair. Here, we used a combination of bioinformatics-based methodologies, as well as experimentally-derived datasets, that reveal the existence of a novel short HP1γ (CBX3) isoform, named here sHP1γ, generated by alternative splicing of the CBX3 locus. The sHP1γ mRNA encodes a protein composed of 101 residues and lacks the C-terminal chromoshadow domain (CSD) that is required for dimerization and heterodimerization in the previously described 183 a. a HP1γ protein. Fold recognition, order-to-disorder calculations, threading, homology-based molecular modeling, docking, and molecular dynamic simulations show that the sHP1γ is comprised of a CD flanked by intrinsically disordered regions (IDRs) with an IDR-CD-IDR domain organization and likely retains the ability to bind to the H3K9Me3. Both qPCR analyses and mRNA-seq data derived from large-scale studies confirmed that sHP1γ mRNA is expressed in the majority of human tissues at approximately constant ratios with the chromoshadow domain containing isoform. However, sHP1γ mRNA levels appear to be dysregulated in different cancer types. Thus, our data supports the notion that, due to the existence of functionally different isoforms, the regulation of HP1γ-mediated functions is more complex than previously anticipated.

Author List

Mathison A, Milech De Assuncao T, Dsouza NR, Williams M, Zimmermann MT, Urrutia R, Lomberk G

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Thiago Milech De Assuncao Research Scientist II in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alternative Splicing
Animals
Binding Sites
CHO Cells
Chromosomal Proteins, Non-Histone
Cricetinae
Cricetulus
Gene Expression Regulation, Neoplastic
HeLa Cells
Histones
Humans
Insulin-Secreting Cells
Protein Binding
Protein Transport