Publications by authors named "Christopher J Terranova"

4 Publications

  • Page 1 of 1

Chromatin state profiling reveals PRC2 inhibition as a therapeutic target in NRAS-mutant melanoma.

Mol Cell Oncol 2021 27;8(5):1986350. Epub 2021 Oct 27.

Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Recently, we have generated 284 epigenomic maps in melanoma. Using chromatin state profiling we identify an association of -mutants with bivalent Histone H3 lysine 27 trimethylation (H3K27me3) and broad H3K4me3 domains. Reprogramming of bivalent H3K27me3 occurs on critical invasive-regulators and its resolution using Enhancer of Zeste Homolog 2 (EZH2) inhibition reduces invasive capacity and tumor burden in mutant patient samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/23723556.2021.1986350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632323PMC
October 2021

Reprogramming of H3K9bhb at regulatory elements is a key feature of fasting in the small intestine.

Cell Rep 2021 11;37(8):110044

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

β-hydroxybutyrate (β-OHB) is an essential metabolic energy source during fasting and functions as a chromatin regulator by lysine β-hydroxybutyrylation (Kbhb) modification of the core histones H3 and H4. We report that Kbhb on histone H3 (H3K9bhb) is enriched at proximal promoters of critical gene subsets associated with lipolytic and ketogenic metabolic pathways in small intestine (SI) crypts during fasting. Similar Kbhb enrichment is observed in Lgr5 stem cell-enriched epithelial spheroids treated with β-OHB in vitro. Combinatorial chromatin state analysis reveals that H3K9bhb is associated with active chromatin states and that fasting enriches for an H3K9bhb-H3K27ac signature at active metabolic gene promoters and distal enhancer elements. Intestinal knockout of Hmgcs2 results in marked loss of H3K9bhb-associated loci, suggesting that local production of β-OHB is responsible for chromatin reprogramming within the SI crypt. We conclude that modulation of H3K9bhb in SI crypts is a key gene regulatory event in response to fasting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.110044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8668154PMC
November 2021

Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy.

Cell Rep 2021 07;36(3):109410

Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address:

The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369408PMC
July 2021

Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression.

Cell Rep 2017 04;19(4):875-889

Division of Cancer Medicine, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address:

The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.03.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473172PMC
April 2017
-->