Transcription Factor Occupancy Can Mediate Active Turnover of DNA Methylation at Regulatory Regions

Feldmann, Angelika; Ivanek, Robert; Murr, Rabih; Gaidatzis, Dimos; Burger, Lukas; Schübeler, Dirk
December 2013
PLoS Genetics;Dec2013, Vol. 9 Issue 12, p1
Academic Journal
Distal regulatory elements, including enhancers, play a critical role in regulating gene activity. Transcription factor binding to these elements correlates with Low Methylated Regions (LMRs) in a process that is poorly understood. Here we ask whether and how actual occupancy of DNA-binding factors is linked to DNA methylation at the level of individual molecules. Using CTCF as an example, we observe that frequency of binding correlates with the likelihood of a demethylated state and sites of low occupancy display heterogeneous DNA methylation within the CTCF motif. In line with a dynamic model of binding and DNA methylation turnover, we find that 5-hydroxymethylcytosine (5hmC), formed as an intermediate state of active demethylation, is enriched at LMRs in stem and somatic cells. Moreover, a significant fraction of changes in 5hmC during differentiation occurs at these regions, suggesting that transcription factor activity could be a key driver for active demethylation. Since deletion of CTCF is lethal for embryonic stem cells, we used genetic deletion of REST as another DNA-binding factor implicated in LMR formation to test this hypothesis. The absence of REST leads to a decrease of hydroxymethylation and a concomitant increase of DNA methylation at its binding sites. These data support a model where DNA-binding factors can mediate turnover of DNA methylation as an integral part of maintenance and reprogramming of regulatory regions.


Related Articles

  • Establishment of epigenetic patterns in development. Leeb, Martin; Wutz, Anton // Chromosoma;Jun2012, Vol. 121 Issue 3, p251 

    The distinct cell types of the body are established from the fertilized egg in development and assembled into functional tissues. Functional characteristics and gene expression patterns are then faithfully maintained in somatic cell lineages over a lifetime. On the molecular level, transcription...

  • An expansive human regulatory lexicon encoded in transcription factor footprints. Neph, Shane; Vierstra, Jeff; Stergachis, Andrew B.; Reynolds, Alex P.; Haugen, Eric; Vernot, Benjamin; Thurman, Robert E.; John, Sam; Sandstrom, Richard; Johnson, Audra K.; Maurano, Matthew T.; Humbert, Richard; Rynes, Eric; Wang, Hao; Vong, Shinny; Lee, Kristen; Bates, Daniel; Diegel, Morgan; Roach, Vaughn; Dunn, Douglas // Nature;9/6/2012, Vol. 489 Issue 7414, p83 

    Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory...

  • microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming. Guo, Xudong; Liu, Qidong; Wang, Guiying; Zhu, Songcheng; Gao, Longfei; Hong, Wujun; Chen, Yafang; Wu, Minjuan; Liu, Houqi; Jiang, Cizhong; Kang, Jiuhong // Cell Research;Jan2013, Vol. 23 Issue 1, p142 

    Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during...

  • Extensive epigenetic reprogramming in human somatic tissues between fetus and adult. Yuen, Ryan K. C.; Neumann, Sarah M. A.; Fok, Alexandra K.; Peñaherrera, Maria S.; McFadden, Deborah E.; Robinson, Wendy P.; Kobor, Michael S. // Epigenetics & Chromatin;2011, Vol. 4 Issue 1, p7 

    Background: Development of human tissue is influenced by a combination of intrinsic biological signals and extrinsic environmental stimuli, both of which are mediated by epigenetic regulation, including DNA methylation. However, little is currently known of the normal acquisition or loss of...

  • Nanog1 in NTERA-2 and Recombinant NanogP8 from Somatic Cancer Cells Adopt Multiple Protein Conformations and Migrate at Multiple M.W Species. Liu, Bigang; Badeaux, Mark D.; Choy, Grace; Chandra, Dhyan; Shen, Irvin; Jeter, Collene R.; Rycaj, Kiera; Lee, Chia-Fang; Person, Maria D.; Liu, Can; Chen, Yueping; Shen, Jianjun; Jung, Sung Yun; Qin, Jun; Tang, Dean G. // PLoS ONE;Mar2014, Vol. 9 Issue 3, p1 

    Human Nanog1 is a 305-amino acid (aa) homeodomain-containing transcription factor critical for the pluripotency of embryonic stem (ES) and embryonal carcinoma (EC) cells. Somatic cancer cells predominantly express a retrogene homolog of Nanog1 called NanogP8, which is ∼99% similar to Nanog...

  • Methylcap-Seq Reveals Novel DNA Methylation Markers for the Diagnosis and Recurrence Prediction of Bladder Cancer in a Chinese Population. Yangxing Zhao; Shicheng Guo; Jinfeng Sun; Zhaohui Huang; Tongyu Zhu; Hongyu Zhang; Jun Gu; Yinghua He; Wei Wang; Kelong Ma; Jina Wang; Jian Yu // PLoS ONE;Apr2012, Vol. 7 Issue 4, p1 

    Purpose: There is a need to supplement or supplant the conventional diagnostic tools, namely, cystoscopy and B-type ultrasound, for bladder cancer (BC). We aimed to identify novel DNA methylation markers for BC through genome-wide profiling of BC cell lines and subsequent methylation-specific...

  • Association of modified cytosines and the methylated DNA-binding protein MeCP2 with distinctive structural domains of lampbrush chromatin. Morgan, Garry; Jones, Peter; Bellini, Michel // Chromosome Research;Dec2012, Vol. 20 Issue 8, p925 

    We have investigated the association of DNA methylation and proteins interpreting methylation state with the distinctive closed and open chromatin structural domains that are directly observable in the lampbrush chromosomes (LBCs) of amphibian oocytes. To establish the distribution in LBCs of...

  • An atypical component of RNA-directed DNA methylation machinery has both DNA methylation-dependent and -independent roles in locus-specific transcriptional gene silencing. Liu, Jun; Bai, Ge; Zhang, Cuijun; Chen, Wei; Zhou, Jinxing; Zhang, Suwei; Chen, Qing; Deng, Xin; He, Xin-Jian; Zhu, Jian-Kang // Cell Research;Dec2011, Vol. 21 Issue 12, p1691 

    RNA-directed DNA methylation (RdDM) is an important de novo DNA methylation pathway in plants. RdDM mediates the transcriptional silencing of many endogenous genomic loci, most of which are transposon related. A forward genetics screen identified DTF1 (DNA-binding transcription factor 1) as a...

  • The CXXC-TET bridge - mind the methylation gap! Dunican, Donncha S; Pennings, Sari; Meehan, Richard R // Cell Research;Aug2013, Vol. 23 Issue 8, p973 

    CG-rich DNA 'reader' proteins that bind non-methylated CpG sequences have emerged as critical factors to the process of cell differentiation and development. In a recent paper in Nature, Ko et al. show that the CXXC domain protein, IDAX, plays a crucial role as a CG-rich DNA-binding factor in...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics