Dataset Information

Inter-Strain Epigenomic Profiling Reveals a Candidate IAP Master Copy in C3H Mice.

ABSTRACT: Insertions of endogenous retroviruses cause a significant fraction of mutations in inbred mice but not all strains are equally susceptible. Notably, most new Intracisternal A particle (IAP) ERV mutagenic insertions have occurred in C3H mice. We show here that strain-specific insertional polymorphic IAPs accumulate faster in C3H/HeJ mice, relative to other sequenced strains, and that IAP transcript levels are higher in C3H/HeJ embryonic stem (ES) cells compared to other ES cells. To investigate the mechanism for high IAP activity in C3H mice, we identified 61 IAP copies in C3H/HeJ ES cells enriched with H3K4me3 (a mark of active promoters) and, among those tested, all are unmethylated in C3H/HeJ ES cells. Notably, 13 of the 61 are specific to C3H/HeJ and are members of the non-autonomous 1Δ1 IAP subfamily that is responsible for nearly all new insertions in C3H. One copy is full length with intact open reading frames and hence potentially capable of providing proteins in trans to other 1Δ1 elements. This potential "master copy" is present in other strains, including 129, but its 5' long terminal repeat (LTR) is methylated in 129 ES cells. Thus, the unusual IAP activity in C3H may be due to reduced epigenetic repression coupled with the presence of a master copy.

SUBMITTER: Rebollo R

PROVIDER: S-EPMC7411935 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inter-Strain Epigenomic Profiling Reveals a Candidate IAP Master Copy in C3H Mice.

Rebollo Rita R Galvão-Ferrarini Mariana M Gagnier Liane L Zhang Ying Y Ferraj Ardian A Beck Christine R CR Lorincz Matthew C MC Mager Dixie L DL

Viruses 20200721 7

Insertions of endogenous retroviruses cause a significant fraction of mutations in inbred mice but not all strains are equally susceptible. Notably, most new Intracisternal A particle (IAP) ERV mutagenic insertions have occurred in C3H mice. We show here that strain-specific insertional polymorphic IAPs accumulate faster in C3H/HeJ mice, relative to other sequenced strains, and that IAP transcript levels are higher in C3H/HeJ embryonic stem (ES) cells compared to other ES cells. To investigate t ...[more]

PMID: 32708087

Similar Datasets

Project description:Coordinated experiments focused on transcriptional responses and chromatin states are well-equipped to capture different epigenomic and transcriptomic levels governing the circuitry of a regulatory network. We propose a workflow for the genome-wide identification of epigenomic and transcriptional cooperation to elucidate transcriptional networks in cancer. Gene promoter annotation in combination with network analysis and sequence-resolution of enriched transcriptional motifs in epigenomic data reveals transcription factor families that act synergistically with epigenomic master regulators. By investigating complementary omics levels, a close teamwork of the transcriptional and epigenomic machinery was discovered. The discovered network is tightly connected and surrounds the histone lysine demethylase KDM3A, basic helix-loop-helix factors MYC, HIF1A, and SREBF1, as well as differentiation factors AP1, MYOD1, SP1, MEIS1, ZEB1, and ELK1. In such a cooperative network, one component opens the chromatin, another one recognizes gene-specific DNA motifs, others scaffold between histones, cofactors, and the transcriptional complex. In cancer, due to the ability to team up with transcription factors, epigenetic factors concert mitogenic and metabolic gene networks, claiming the role of a cancer master regulators or epioncogenes. Significantly, specific histone modification patterns are commonly associated with open or closed chromatin states, and are linked to distinct biological outcomes by transcriptional activation or repression. Disruption of patterns of histone modifications is associated with the loss of proliferative control and cancer. There is tremendous therapeutic potential in understanding and targeting histone modification pathways. Thus, investigating cooperation of chromatin remodelers and the transcriptional machinery is not only important for elucidating fundamental mechanisms of chromatin regulation, but also necessary for the design of targeted therapeutics.

Project description:BackgroundTranscriptional dysregulation drives cancer formation but the underlying mechanisms are still poorly understood. Renal cell carcinoma (RCC) is the most common malignant kidney tumor which canonically activates the hypoxia-inducible transcription factor (HIF) pathway. Despite intensive study, novel therapeutic strategies to target RCC have been difficult to develop. Since the RCC epigenome is relatively understudied, we sought to elucidate key mechanisms underpinning the tumor phenotype and its clinical behavior.MethodsWe performed genome-wide chromatin accessibility (DNase-seq) and transcriptome profiling (RNA-seq) on paired tumor/normal samples from 3 patients undergoing nephrectomy for removal of RCC. We incorporated publicly available data on HIF binding (ChIP-seq) in a RCC cell line. We performed integrated analyses of these high-resolution, genome-scale datasets together with larger transcriptomic data available through The Cancer Genome Atlas (TCGA).FindingsThough HIF transcription factors play a cardinal role in RCC oncogenesis, we found that numerous transcription factors with a RCC-selective expression pattern also demonstrated evidence of HIF binding near their gene body. Examination of chromatin accessibility profiles revealed that some of these transcription factors influenced the tumor's regulatory landscape, notably the stem cell transcription factor POU5F1 (OCT4). Elevated POU5F1 transcript levels were correlated with advanced tumor stage and poorer overall survival in RCC patients. Unexpectedly, we discovered a HIF-pathway-responsive promoter embedded within a endogenous retroviral long terminal repeat (LTR) element at the transcriptional start site of the PSOR1C3 long non-coding RNA gene upstream of POU5F1. RNA transcripts are induced from this promoter and read through PSOR1C3 into POU5F1 producing a novel POU5F1 transcript isoform. Rather than being unique to the POU5F1 locus, we found that HIF binds to several other transcriptionally active LTR elements genome-wide correlating with broad gene expression changes in RCC.InterpretationIntegrated transcriptomic and epigenomic analysis of matched tumor and normal tissues from even a small number of primary patient samples revealed remarkably convergent shared regulatory landscapes. Several transcription factors appear to act downstream of HIF including the potent stem cell transcription factor POU5F1. Dysregulated expression of POU5F1 is part of a larger pattern of gene expression changes in RCC that may be induced by HIF-dependent reactivation of dormant promoters embedded within endogenous retroviral LTRs.

Dataset Information

Inter-Strain Epigenomic Profiling Reveals a Candidate IAP Master Copy in C3H Mice.

Publications

Inter-Strain Epigenomic Profiling Reveals a Candidate IAP Master Copy in C3H Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets