Off-campus UNL users: To download campus access dissertations, please use the following link to log into our proxy server with your NU ID and password. When you are done browsing please remember to return to this page and log out.

Non-UNL users: Please talk to your librarian about requesting this dissertation through interlibrary loan.

From histone modification to gene repression: Epigenetic regulation by holocarboxylase synthetase-containing repression complex and fad-dependent lysine specific demethylase

Dandan Liu, University of Nebraska - Lincoln

Abstract

Histones undergo different types of post-translational modifications that have been linked to a variety of biological processes and disease states. Histone acetylation and methylation are well characterized modifications with respect to regulation of chromatin structure and transcription. Histone acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is linked with gene activation. Here we introduce a novel paradigm suggesting that holocarboxylase synthetase (HLCS), the sole biotin protein ligase in the human genome, recruits nuclear receptor corepressor (N-CoR) and HDAC1 to chromatin, thereby contributing toward the removal of lysine (K)-9 acetylated histone H3 (H3K9ac) gene activation marks and the repression of repeats, linking biotin metabolism with histone acetylation. We observed that (1) HLCS interacts physically with N-CoR and HDAC1; (2) HLCS overexpression induces a significant decrease in the abundance of H3K9ac marks in long terminal repeats (LTRs) 15 and 22 decreasing LTR expression; and (3) HLCS-dependent repression of pericentromeric alpha satellite repeats. We conclude that interactions of HLCS with N-CoR and HDAC1 contribute toward transcriptional repression of repeats. Unlike histone acetylation, histone methylation is commonly associated with either transcriptional activation or repression and is regulated by the opposing activities of histone methyltransferases and demethylases. Lysine specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent demethylase that catalyzes the removal of methyl groups from lysine-4 in histone H3 (H3K4me1, H3K4me2), thereby mediating gene repression. We cultured cells in riboflavin-defined media providing riboflavin at levels representing moderately deficient, sufficient, and supplemented in humans. LSD1 activity depends on the concentrations of the FAD precursor, riboflavin, in cell culture media, and riboflavin deficiency causes de-repression of albumin and pro-inflammatory cytokines in human HepG2 and Jurkat cells, respectively. Loss of LSD1 activity is associated with a significant increase in the abundance of H3K4me2 marks, leading to an aberrant up-regulation of target gene expression. In conclusion, riboflavin affects gene regulation by epigenetic mechanisms, mediated by a loss of LSD1 activity.^

Subject Area

Biology, Molecular|Health Sciences, General|Health Sciences, Nutrition

Recommended Citation

Liu, Dandan, "From histone modification to gene repression: Epigenetic regulation by holocarboxylase synthetase-containing repression complex and fad-dependent lysine specific demethylase" (2014). ETD collection for University of Nebraska - Lincoln. AAI3617473.
http://digitalcommons.unl.edu/dissertations/AAI3617473

Share

COinS