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Humaira Gowher

Humaira Gowher Profile Picture

Assistant Professor, Department of Biochemistry
PhD (Dr. rer. nat.), JLU, Germany

Contact Info:

Training Group(s):
Chromatin and Regulation of Gene Expression
Computational and Systems Biology

Current Research Interests:

The expression of a large cohort of genes is dynamically regulated during normal cell differentiation, cancer progression and as a result of an exposure to environmental toxins. This change in expression is mediated by changes in the epigenetic state of these genes. Thus, inspection of the regulation of epigenetic processes like DNA methylation is the key to understanding cellular differentiation and developmental origin of disease. DNA methylation is a heritable and reversible epigenetic phenomenon which is associated largely with gene repression. My research is focused on understanding the regulation of DNA methylation including studies of the mechanism of action of the enzymes DNA methyltransferases (MTase) and mechanisms that modulate their activity. Given the DNA MTases, Dnmt3a and 3b are highly expressed in embryonic stages and in embryonic stem (ES) cells, for our study, we will use mouse embryonic stem cell differentiation as a model system.

In an epigenetic regulatory network, several histone modifications have been shown to direct DNA methylation and vice versa. Our work will further elaborate on these connections with emphasis on the interaction between histone lysine methylation and DNA methylation. The possible role of RNA mediated targeting of DNA MTases is another subject of investigation. In parallel, we will continue investigating the mechanism of the insulator protein Vezf1, which regulates the expression and splicing of Dnmt3b in mouse ES cells. My previous studies in Vezf1 -/- ES cells have shown widespread loss of DNA methylation, including at CpG islands, in the vicinity of several tissue specific genes that regulate developmental programs.  New studies will investigate the sites that lost methylation in Vezf1 -/- ES cells as specific targets of Dnmt3b.

Hypermethylation of the specific gene promoters has been reported in almost all cancers. However the mechanisms that define target methylation have not been completely understood. Based on the speculation that under various stimuli, the global gene expression and therefore the composition of protein complexes in the cells is altered, we will identify the interaction partners of the DNA MTases in normal v/s the cancer cells and further investigate their role in target site specificity of the DNA MTases.

There are about 40 alternatively spliced isoforms of the human DNMT3B, several of which show tissue specific and tumor-specific expression. Very little is known about the mechanism/cofactors that regulate expression, alternative splicing and activity of DNA MTases during development of normal cells or cancer cells. We will perform a systematic investigation of the specific roles of various isoforms of Dnmt3b in normal and in cancer cells. Further, we will identify the transcription factor network that regulates the expression of Dnmt3 enzymes in tissue-specific manner.

Selected Publications:

Gowher, H., Brick, K. and Felsenfeld, G. Pausing of elongating Pol II stimulated by Vezf1 regulates alternative splicing. (2012) Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2370-5.

Dickson J., Gowher H., Strogantsev R., Gaszner M., Hair A., Felsenfeld G. and West A.G. (2010) VEZF1 elements mediate protection from DNA methylation PLoS Genet. 2010 Jan;6(1) Bold= authors contributed equally Gowher, H., Stuhlmann, H. and Felsenfeld, G. (2008).

Vezf1 Regulates Genomic DNA Methylation Through its Effects on Expression of DNA Methyltransferase Dnmt3b. Genes Dev. 2008 Aug 1;22(15):2075-84 

 Gowher, H., Loutchanwoot, P., Vorobjeva, O., Handa, V., Jurkowska, R. Z., Jurkowski, T. P., and Jeltsch, A. (2006). Mutational analysis of the catalytic domain of the murine Dnmt3a DNA-(cytosine C5)-methyltransferase. J Mol Biol 357, 928-941.

Gowher, H., Stockdale, C. J., Goyal, R., Ferreira, H., Owen-Hughes, T., and Jeltsch, A. (2005b). De novo methylation of nucleosomal DNA by the mammalian Dnmt1 and Dnmt3A DNA methyltransferases. Biochemistry 44, 9899-9904.

Gowher, H., Liebert, K., Hermann, A., Xu, G., and Jeltsch, A. (2005a). Mechanism of stimulation of catalytic activity of Dnmt3A and Dnmt3B DNA-(cytosine-C5)- methyltransferases by Dnmt3L. J Biol Chem 280, 13341-13348.

Ghirlando R, Giles K, Gowher H, Xiao T, Xu Z, Yao H, Felsenfeld G. (2012) Chromatin domains, insulators, and the regulation of gene expression. Biochim Biophys Acta. 2012 Jul;1819(7):644-51

Giles KE, Gowher H, Ghirlando R, Jin C, Felsenfeld G. (2010) Chromatin Boundaries, Insulators, and Long-Range Interactions in the Nucleus. Cold Spring Harb Symp Quant Biol. 2010, Nov 3.

Gowher, H., and Jeltsch, A. (2004). Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy. Cancer Biol Ther 3, 1062-1068.

Hermann, A., Gowher, H., and Jeltsch, A. (2004). Biochemistry and biology of mammalian DNA methyltransferases. Cell Mol Life Sci 61, 2571-2587.   

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