Biological Science Faculty Member
Dr. Brian P. Chadwick
Associate of the Royal College of Science
Ph.D., University College London, 1997
Academic editor: PLoS One
Editorial Advisory Board: Chromosome Research
Research and Professional Interests:
X Chromosome Inactivation (XCI)
XCI is the mammalian form of dosage compensation that serves to balance the levels of X-linked gene expression between the sexes. Early in development, one of the two X chromosomes in females is chosen to become the inactive X chromosome (Xi). Soon thereafter, the long noncoding RNA XIST, triggers a cascade of events that repackage the chosen Xi into facultative heterochromatin, shutting down most gene expression along the length of the chromosome. This altered state is faithfully maintained throughout all subsequent somatic cell divisions, making XCI a classic model of epigenetic gene regulation whereby the two X chromosomes are recognized and acted upon as different within the same nucleus.
My lab is interested in the organization and maintenance of chromatin on the human Xi. Our current research focuses on three aspects of the Xi:
- Large tandem repeat DNA on the X chromosome that adopt a Xi-specific euchromatin organization that is bound by the epigenetic organizer protein CTCF. These sequences physically interact despite being millions of bases pairs apart, and are candidate chromosome folding elements.
- The role of chromatin proteins, histone variants and histone modifications in folding, compacting and silencing the Xi.
- The role of chromatin proteins that transiently associate with the Xi during the cell cycle, as candidates for maintenance of chromatin states.
Macrosatellites are large tandem repeat DNA consisting of a variable number of tandem repeat units, typically >1.0 kb in size, that are largely restricted to specific locations on one or two of our chromosomes. We are primarily focused on two such macrosatellites; DXZ4 located at Xq23 and D4Z4 found in the subtelomeric regions of chromosomes 4q and 10q. Both macrosatellites show similar interesting changes to their epigenomic organization in response to triggering events, which in the case of D4Z4 can result in onset of facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant disease.
Sun, Z., & Chadwick B. P. (2018) Loss of SETDB1 decompacts the inactive X chromosome in part through reactivation of an enhnacer in the IL1RAPL1 gene. Epigenetics & Chromatin 11:45:1-20
Westervelt, N., & Chadwick, B. P. (2018) Characterization of the ICCE repeat in mammals reveals an evolutionary relationship with the DXZ4 macrosatellite through conserved CTCF binding motifs. Genome Biology & Evolution 10(9):2190-2204
Darrow, E. M., Huntley, M. H., Dudchenko, O., Stamenova, E. K., Durand, N. C., Sun, Z., Huang, S.C., Sanborn, A. L., Machol, I., Shamim, M., Seberg, A. P., Lander, E. S., Chadwick, B. P., Aiden E. L. (2016). Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture. Proceedings of the National Academy of Sciences of the USA 113 (31):E4504-12
Das, D. & Chadwick, B. (2016). Influence of repressive histone and DNA methylation upon D4Z4 transcription in non-myogenic cells. PLoS ONE (7) e0160022.
Kusi-Appiah, A. E., Lowry, T. W., Darrow, E. M., Wilson, K., Chadwick, B. P., Davidson, M. W., & Lenhert, S. (2015). Quantitative dose–response curves from subcellular lipid multilayer microarrays. Lab on a Chip, 15(16), 3397-3404. â€¨â€¨
Figueroa, D., Darrow, E., & Chadwick, B. (2015). Two novel DXZ4-associated long noncoding RNAs show developmental changes in expression coincident with heterochromatin formation at the macrosatellite. Chromosome Research, 23(4), 733-752.
Chadwick, B. (2015). Preface. In Chadwick BP (Ed.), Epigenetics: Current Research and Emerging Trends. Caister Academic Press. â€¨â€¨
Darrow, E., & Chadwick, B. (2015). Ingenious genes: the diverse roles of long noncoding RNA in regulatory processes. In Chadwick BP (Ed.), Epigenetics: Current Research and Emerging Trends. Caister Academic Press.
Das, S., & Chadwick, B. (2015). The long and short of Facioscapulohumeral muscular dystrophy. In Chadwick BP (Ed.), Epigenetics: Current Research and Emerging Trends. Caister Academic Press. â€¨â€¨
Sun, Z., & Chadwick, B. (2015). SETting up the epigenome through the histone methyltransferase SETDB1. In Chadwick BP (Ed.), Epigenetics: Current Research and Emerging Trends. Caister Academic Press. â€¨â€¨
Darrow, E. M., Seberg, A. P., Das, S., Figueroa, D. M., Sun, Z., Moseley, S. C., & Chadwick, B. P. (2014). A region of euchromatin coincides with an extensive tandem repeat on the mouse (Mus musculus) inactive X chromosome. Chromosome Research, 22: 335-350
Darrow, E. M., & Chadwick, B. P. (2014). A novel tRNA variable number tandem repeat at human chromosome 1q23.3 is implicated as a boundary element based on conservation of a CTCF motif in mouse. Nucleic Acids Research, 42(10): 6421-6435
Culver-Cochran, A. E., & Chadwick, B. P. (2013). Loss of WSTF results in spontaneous fluctuations of heterochromatin formation and resolution, combined with substantial changes to gene expression. BMC Genomics, 14:740, 1 to 18.
Darrow, E. M., & Chadwick, B. P. (2013). Boosting transcription by transcription: enhancer-associated transcripts. Chromosome Res.21(6-7):713-724
Chadwick, B. P., & Scott, K. C. (2013). Molecular versatility: The many faces and functions of noncoding RNA. Chromosome Res.21(6-7):555-559. (Front Cover)
Culver-Cochran, A. E. and Chadwick, B. P. (2012). The WSTF-ISWI Chromatin Remodeling Complex transiently associates with the human inactive X chromosome during late S-phase prior to BRCA1 and gamma-H2AX. PLoS ONE, (7) e50023
Horakova, A. H., S. C. Moseley, C. R. McLaughlin, D. C. Tremblay, and B. P. Chadwick. (2012). The macrosatellite DXZ4 mediates CTCF-dependent long-range intrachromosomal interactions on the human inactive X chromosome. Human Molecular Genetics. 21(20):4367-4377
Talbert, P. B., K. Ahmad, G. Almouzni, J. Ausio, F. Berger, P. L. Bhalla, W. M. Bonner, W. Z. Cande, B. P. Chadwick, S. W. Chan, G. A. Cross, L. Cui, S. I. Dimitrov, D. Doenecke, J. M. Eirin-Lopez, M. A. Gorovsky, S. B. Hake, B. A. Hamkalo, S. Holec, S. E. Jacobsen, K. Kamieniarz, S. Khochbin, A. G. Ladurner, D. Landsman, J. A. Latham, B, Loppin, H. S. Malik, W. F. Marzluff, J. R. Pehrson, J. Postberg, R. Schneider, M. B. Singh, M. M. Smith, E. Thompson, M. E. Torres-Padilla, D. J. Tremethick, B. M. Turner, J. H. Waterborg, H. Wollmann, R. Yelagandula, B. Zhu, and S. Henikoff. (2012). A unified phylogeny-based nomenclature for histone variants. Epigenetics and Chromatin 5:7.
Horakova, A. H., J. M. Calabrese, C. M. McLaughlin, D. C. Tremblay, T. Magnuson, and B. P. Chadwick. (2012). The mouse DXZ4 homolog retains Ctcf binding and proximity to Pls3 despite substantial organizational differences compared to the primate macrosatellite. Genome Biology 13:R70
Moseley, S. C., R. Rizkallah, D. C. Tremblay, B. R. Anderson, M. M. Hurt, and B. P. Chadwick. (2012). YY1 associates with the macrosatellite DXZ4 on the inactive X chromosome and binds with CTCF to a hypomethylated form in some male carcinomas. Nucleic Acids Research 40:1596–1608.
Chadwick, B. P. (2011). Macrosatellite epigenetics. Pages 143-159 in J. M. Craig and N. C. Wong, editors. Epigenetics: A Reference Manual. Caister Academic Press, Norfolk, UK.
Tremblay, D. C., S. Moseley, and B. P. Chadwick. (2011). Variation in array size, monomer composition and expression of the macrosatellite DXZ4. PLoS ONE 6:e18969.
McLaughlin, C. R., and B. P. Chadwick. (2011). Characterization of DXZ4 conservation in primates implies important functional roles for CTCF binding, array expression and tandem repeat organization on the X chromosome. Genome Biology 12:R37.
Tremblay, D. C., G. Alexander, Jr., S. Moseley, and B. P. Chadwick. (2010). Expression, tandem repeat copy number variation and stability of four macrosatellite arrays in the human genome. BMC Genomics 11:632.
Chadwick B. P. (2009). Macrosatellite epigenetics: the two faces of DXZ4 and D4Z4. Chromosoma 118:675-681.
(Selected other pre-FSU publications)
Chadwick, B. P. (2008). DXZ4 chromatin adopts an opposing conformation to that of the surrounding chromosome and acquires a novel inactive X specific role involving CTCF and anti-sense transcripts. Genome Research 18:1259-1269.
Majumder, P., J. A. Gomez, B. P. Chadwick, and J. M. Boss. (2008). The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions. Journal of Experimental Medicine 205:785-798.
Chadwick, B. P. (2007). Variation in Xi chromatin organization and correlation of the H3K27me3 chromatin territories to transcribed sequences by microarray analysis. Chromosoma 116:147-157.
Xiao, C., J. A. Sharp, M. Kawahara, A. R. Davalos, M. J. Difilippantonio, Y. Hu, W. Li, L. Cao, K. Buetow, T. Ried, B. P. Chadwick, C. X. Deng, and B. Panning. (2007). The XIST noncoding RNA functions independently of BRCA1 in X inactivation. Cell 128:977-989.
Abbott, D. W., B. P. Chadwick, A. A. Thambirajah, and J. Ausio. (2005). Beyond the Xi: MacroH2A chromatin distribution and post-translational modification in an avian system. Journal of Biological Chemistry 280:16437-16445.
Chadwick, B. P., and T. F. Lane. 2005. BRCA1 associates with the Xi in late S-phase, coupled with transient H2AX phosphorylation. Chromosoma 114:432-439.
Chadwick, B. P., and H. F. Willard. (2004). Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome. Proceedings of the National Academy of Sciences of the USA 101:17450-17455.
Chadwick, B. P., and H. F. Willard. (2003). Chromatin of the Barr body is differentially histone methylated and enriched for HP1, histone H1 and HMG-I/Y, while many chromatin proteins are largely excluded. Human Molecular Genetics 12:2167-2178.
Chadwick, B. P., and H. F. Willard. (2002). Cell cycle-dependent localization of macroH2A in chromatin of the inactive X chromosome. Journal of Cell Biology 157:1113-1123.
Chadwick, B. P., and H. F. Willard. (2001). A novel chromatin protein, distantly related to histone H2A, is largely excluded from the inactive X chromosome. Journal of Cell Biology 152:375-384.