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Published on: October 27, 2020
Global Gene Expression Regulation Mediated by TGFβ Through H3K9me3 Mark
Ankit Naik1, Nidhi Dalpatraj1, Noopur Thakur1
1Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad, Gujarat, India.
Background:
Epigenetic alterations play an important part in carcinogenesis. Different biological responses, including cell proliferation, migration, apoptosis, invasion, and senescence, are affected by epigenetic alterations in cancer. In addition, growth factors, such as transforming growth factor beta (TGFβ) are important regulators of tumorigenesis. Our understanding of the interplay between the epigenetic bases of tumorigenesis and growth factor signaling in tumorigenesis is rudimentary. Some studies suggest a link between TGFβ signaling and the heterochromatinizing histone mark H3K9me3. There is evidence for signal-dependent interactions between R-Smads and histone methyltransferases. However, the effects of TGFβ signaling on genome wide H3K9me3 landscape remains unknown. Our research examines TGFβ -induced genome-wide H3K9me3 in prostate cancer.
Method:
Chromatin-Immunoprecipitation followed by sequencing was performed to analyze genome-wide association of H3K9me3 epigenetic mark. DAVID Functional annotation tool was utilized to understand the involvement of different Biological Processes and Molecular Function. MEME-ChIP tool was also used to analyze known and novel DNA-binding motifs.
Results:
H3K9me3 occupancy appears to increase at intronic regions after short-term (6 hours) TGFβ stimulation and at distal intergenic regions during long-term stimulation (24 hours). We also found evidence for a possible association of SLC transporters with H3K9me3 mark in presence of TGFβ during tumorigenesis. No direct correlation was found between the occupancy of H3K9me3 mark and the expression of various genes. The epigenetic mechanisms-mediated regulation of gene expression by TGFβ was concentrated at promoters rich in SRY and FOXJ3 binding sites.
Conclusion:
Our results point toward a positive association of oncogenic function of TGFβ and the H3K9me3 mark and provide a context to the role of H3K9me3 in TGFβ-induced cell migration and cell adhesion. Interestingly, these functions of TGFβ through H3K9me3 mark regulation seem to depend on transcriptional activation in contrast to the conventionally known repressive nature of H3K9me3.
Insights
Transforming growth factor beta (TGFβ) influences prostate cancer by altering the H3K9me3 epigenetic mark. This study reveals TGFβ-induced H3K9me3 changes in specific genomic regions, impacting cell migration and adhesion.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- Epigenetic alterations are crucial in cancer development, affecting key cellular processes.
- Transforming growth factor beta (TGFβ) signaling is a known regulator of tumorigenesis.
- The interplay between TGFβ signaling and epigenetic modifications, specifically H3K9me3, in cancer is not well understood.
Purpose of the Study:
- To investigate the genome-wide effects of TGFβ signaling on the H3K9me3 epigenetic landscape in prostate cancer.
- To explore the functional consequences of TGFβ-induced H3K9me3 alterations in tumorigenesis.
Main Methods:
- Chromatin-Immunoprecipitation followed by sequencing (ChIP-seq) to map H3K9me3 occupancy genome-wide.
- Bioinformatic analysis using DAVID and MEME-ChIP tools for functional annotation and motif discovery.
Main Results:
- TGFβ stimulation led to increased H3K9me3 occupancy in intronic regions (6 hours) and distal intergenic regions (24 hours).
- A potential association between SLC transporters and H3K9me3 was observed in the presence of TGFβ.
- No direct correlation was found between H3K9me3 occupancy and gene expression, but regulation was linked to SRY and FOXJ3 binding sites.
Conclusions:
- TGFβ signaling positively associates with the oncogenic function of H3K9me3, particularly in cell migration and adhesion.
- TGFβ-mediated H3K9me3 regulation appears to involve transcriptional activation, contrasting with its typical repressive role.
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