Assessment of histone tail modifications and transcriptional profiling during colon cancer progression reveals a global decrease in H3K4me3 activity.
During colon cancer, epigenetic alterations contribute to the dysregulation of major cellular functions and signaling pathways. Modifications in chromatin signatures such as H3K4me3 and H3K9ac, which are associated with transcriptionally active genes, can lead to genomic instability and perturb the expression of gene sets associated with oncogenic processes. In order to further elucidate early pre-tumorigenic epigenetic molecular events driving CRC, we integrated diverse, genome-wide, epigenetic inputs (by high throughput sequencing of RNA, H3K4me3, and H3K9ac) and compared differentially expressed transcripts (DE) and enriched regions (DER) in an in-vivo rat colon cancer progression model. Carcinogen (AOM) effects were detected genome-wide at the RNA (116 DE genes), K9ac (49 DERs including 24 genes) and K4me3 (7678 DERs including 3792 genes) level. RNA-seq differential expression and pathway analysis indicated that interferon-associated innate immune responses were impacted by AOM exposure. Despite extensive associations between K4me3 DERs and colon tumorigenesis (1210 genes were linked to colorectal carcinoma) including FOXO3, GNAI2, H2AFX, MSH2, NR3C1, PDCD4 and VEGFA, these changes were not reflected at the RNA gene expression level during early cancer progression. Collectively, our results indicate that carcinogen-induced changes in gene K4me3 DERs are harbingers of future transcriptional events, which drive malignant transformation of the colon.
Department of Nutrition and Food Science and Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA; Department of Biology, Texas A&M University, College Station, TX 77843, USA.
Karen
K
Triff
Department of Statistics in Texas A&M University, College Station, 77843, TX, USA.
Mathew W
MW
McLean
Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX 77843, USA.
Kranti
K
Konganti
Department of Nutrition and Food Science and Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA.
Jiahui
J
Pang
Department of Nutrition and Food Science and Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA.
Evelyn
E
Callaway
Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX 77843, USA.
Beiyan
B
Zhou
Department of Nutrition and Food Science and Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA; Department of Statistics in Texas A&M University, College Station, 77843, TX, USA; Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX 77843, USA.
Ivan
I
Ivanov
Department of Nutrition and Food Science and Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX 77843, USA. Electronic address: r-chapkin@tamu.edu.
Robert S
RS
Chapkin
D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014158:Transcription, Genetic
D006657:Histones; D009363:Neoplasm Proteins