Regulation of H2B Monoubiquitination Pathway in Breast cancer

by Upasana Bedi
Doctoral thesis
Date of Examination:2014-01-24
Date of issue:2015-01-23
Advisor:Prof. Dr. Steven Johnsen
Referee:Prof. Dr. Gregor Bucher
Referee:Prof. Dr. Holger Reichardt
Persistent Address: http://dx.doi.org/10.53846/goediss-4876

 

 

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Abstract

English

H2B monoubiquitination (H2Bub1) regulation via CDK9-WAC-RNF20/40 axis has been well illustrated. It is interesting to determine the upstream regulators which dictate the process of monoubiquitination of H2B. On further investigation, histone chaperone SUPT6H known to bind P-Ser2 RNAPII was observed to regulate ERα-dependent signaling through H2Bub1 pathway. Perturbation of SUPT6H led to a decrease in H2Bub1 resulting in impaired estrogen-dependent signaling and mesenchymal stem cell differentiation due to increase in the H3K27me3 repressive mark on the promoters of the genes. Moreover, SUPT6H levels were decreased with tumor progression. Together, these data identify SUPT6H as a new epigenetic regulator of ERα activity and cellular differentiation. Further upstream regulator of CDK9, BRD4 was also examined. For the first time, we showed the connection between BRD4 and H2Bub1 pathway. They both regulated the gene expression in a similar fashion and had gene expression-dependent occupancy on the genes. Interruption of this pathway by BRD4 or H2Bub1 depletion resulted in acquisition of EMT and stem cell-like phenotype in mammary epithelial cells. The preliminary data for conditional RNF40 KO in mammary gland also showed increased mammary branching further emphasizing the critical role of H2Bub1 as a tumor suppressor. These important findings could help to harness these epigenetic regulators for anti-cancer therapy.
Keywords: H2Bub1, stem cell, SUPT6H, RNF40
 
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