DNA is highly compacted in the eukaryotic nucleus in the form of chromatin. The basic repeat unit of chromatin is the nucleosome, which consists of 146 bp of DNA spooled around an octamer of histone proteins. Nucleosomes are folded into progressively higher order structures that influence all DNA-driven processes. Histones are subject to numerous post-translational modifications, including acetylation, methylation, phosphorylation, and ubiquitylation, among others. These modifications regulate chromatin folding, as well as the interaction of non-histone proteins with nucleosomes. Histone modification patterns are dynamic and have been proposed to provide an epigenetic code that governs gene transcription, DNA repair, recombination, and replication. Our lab is interested in deciphering this code and determining whether it is limited to histones. To this end, we use molecular, genetic, and biochemical approaches to probe the functions and regulation of several histone modifying enzymes. We have established numerous connections between histone acetyltransferases and histone deacetylases in regulating gene expression. Our most recent studies uncovered an unexpected relationship between a histone methyltransferase, Set1, and kinetochore function in yeast. Other experiments demonstrated that a histone acetyltransferase, GCN5, is required for telomere maintenance during mouse development. These findings indicate that histone modifying enzymes are centrally important not only to establishing specific transcription programs but also to maintaining genomic integrity. Our work suggests that alterations in the activity or expression of these enzymes may contribute to aneuploidies associated with cancer formation. Future projects will test this idea.


Getting Turned On by HATs: Recruitment of histone acetyltransferase (HAT) activities by DNA bound transcription factors activates downstream promoters.

 

Dent Laboratory Publications 2003-2008
(Please note: Sharon Y. Roth is the former name of Sharon Y.R. Dent)

• Lin W, Chen C-H, Behringer RR, Dent SYR. (2008) Proper Gcn5 histone acetyltransferase expression is required for proper anteroposterior patterning of the mouse skeleton. Dev Growth and Diff 2008 in press.



• Riefler GM, Dent SYR, Schumacher JM. (2008) Tousled-mediated activation of the Aurora B kinase does not require touseled kinase activity in vivo. J Biol Chem 2008 Mar 10; [Epub ahead of print].
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/18334486?dopt=Abstract



• Lin W, Zhang Z, Srajer G, Chen YC, Huang M,  Phan HM, Dent SYR. (2008) Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos. Dev Dyn 2008 Mar 10; 237(4):928–40.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/18330926?dopt=Abstract



• Latham JA, Dent SYR. (2007) Cross-regulation of histone modifications. Nat Struct Mol Biol 2007 Nov 5; 14(11):1017–1024.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/17984964?dopt=Abstract



• Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T, Pillus L, Reinberg D, Shi Y, Shiekhatter R, Shilatifard A, Workman J, Zhang Y. (2007) New nomenclature for chromatin-modifying enzymes. Cell 2007; 131:633–6.



• Zhang X, Yuan Z, Zhang Y, Yong S, Salas-Burgos A, Koomen J, Olashaw N, Parsons JT, Yang X-J, Dent SYR, Yao T-P, Lane WS, Seto E. (2007) HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell 2007; 26:197–213.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/17643370?dopt=Abstract



• Chosed R, Dent SYR. (2007) A two-way street: LSD1 regulates chromatin boundary formation in S. pombe and Drosophila. Mol Cell 2007 Apr 27; 26(2):160–2. Review.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/17466618?dopt=Abstract



• Lin W, Srajer G, Evrard YA, Phan HM, Furuta Y, Dent SYR. (2007) Developmental potential of Gcn5(-/-) embryonic stem cells in vivo and in vitro. Dev Dyn 2007 Jun; 236(6):1547–57.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/17440986?dopt=Abstract



• Bu P, Evrard YA, Lozano G, Dent SYR. (2007) Loss of Gcn5 acetyltransferase activity leads to neural tube closure defects and exencephaly in mouse embryos. Mol Cell Biol 2007 May; 27(9):3405–16.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/17325035?dopt=Abstract



• Malavé TM, Dent SYR. (2006) Transcriptional repression by Tup1-Ssn6. Biochem Cell Biol 2006 Aug; 84(4):437–43. Review.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16936817?dopt=Abstract



• Lin W, Dent SYR. (2006) Functions of histone-modifying enzymes in development. Curr Opin Genet Dev 2006 Apr; 16(2):137–42.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16503130?dopt=Abstract



• Davie JK, Dent SYR. (2006) No Spt6, no nucleosomes, no activator required. Mol Cell 2006 Feb 17; 21(4):452–3.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16483927?dopt=Abstract



• Tripic T, Edmondson DG, Davie JK, Strahl BD, Dent SYR. (2006) The Set2 methyltransferase associates with Ssn6 yet Tup1-Ssn6 repression is independent of histone methylation. Biochem Biophys Res Commun 2006 Jan 20; 339(3):905–14.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16329992?dopt=Abstract



• Zhang K, Dent SYR. (2005) Histone modifying enzymes and cancer: going beyond histones. J Cell Biochem 2005 Dec 15; 96(6):1137–48. Review.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16173079?dopt=Abstract



• Zhang K, Lin W, Latham JA, Riefler GM, Schumacher JM, Chan C, Tatchell K, Hawke DH, Kobayashi R, Dent SYR. (2005) The Set1 methyltransferase opposes Ipl1 aurora kinase functions in chromosome segregation. Cell 2005 Sep 9; 122(5):723–34.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16143104?dopt=Abstract



• Phan HM, Xu AW, Coco C, Srajer G, Wyszomierski S, Evrard YA, Eckner R, Dent SYR. (2005) GCN5 and p300 share essential functions during early embryogenesis. Dev Dyn 2005 Aug; 233(4):1337–47.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/15937931?dopt=Abstract



• Davie JK, Dent SYR. (2004) Histone modifications in corepressor functions. Curr Top Dev Biol 2004 59:145–63. Review.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/14975250?dopt=Abstract



• Coombes MM, Briggs KL, Bone JR, Clayman GL, El-Naggar AK, Dent SYR. (2003) Resetting the histone code at CDKN2A in HNSCC by inhibition of DNA methylation. Oncogene 2003 Dec 4; 22(55):8902–11.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/14654786?dopt=Abstract



• Fujii S, Luo RZ, Yuan J, Kadota M, Oshimura M, Dent SYR, Kondo Y, Issa J-P J, Bast RC, Yu Y. (2003) Reactivation of the silenced and imprinted alleles of ARH1 is associated with increased H3 acetylation and decreased H3 lysine 9 methylation. Hum Mol Gene 2003; 12:1791–1800.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/12874100?dopt=Abstract



• Davie JK, Edmondson DG, Coco CB, Dent SYR. (2003) Tup1-Ssn6 interacts with multiple class I histone deacetylases in vivo. J Biol Chem 2003 Dec 12; 278(50):50158–62.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/14525981?dopt=Abstract
  Oligos used in paper: link to page uploaded, titled “Oligo information for paper”



• Liu X. Tesfai J, Evrard YA, Dent SYR, Martinez E. (2003) c-Myc transformation domain recruits the human STAGA complex and requires TRRAP and GCN5 acetylase activity for transcription activation. J Biol Chem 2003 May 30; 278(22):20405–12.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/12660246?dopt=Abstract



• Mukai Y, Davie JK, Dent SYR. (2003) Physical and functional interaction of the yeast corepressor Tup1 with mRNA 5’-triphosphatase. J Biol Chem 2003 May 23; 278(21):18895–901.
  Abstract: http://www.ncbi.nlm.nih.gov/pubmed/12637515?dopt=Abstract