title: Two novel DXZ4-associated long noncoding RNAs show developmental changes in expression coincident with heterochromatin formation at the human (Homo sapiens) macrosatellite repeat.
abstract: On the male X and female active X chromosome (Xa), the macrosatellite repeat (MSR) DXZ4 is packaged into constitutive heterochromatin characterized by CpG methylation and histone H3 tri-methylated at lysine-9 (H3K9me3). In contrast, DXZ4 on the female inactive X chromosome (Xi), is packaged into euchromatin, is bound by the architectural protein CCCTC-binding factor, and mediates Xi-specific long-range cis contact with similarly packaged tandem repeats on the Xi. In cancer, male DXZ4 can inappropriately revert to a Xi-like state and other MSRs have been reported to adopt alternate chromatin configurations in response to disease. Given this plasticity, we sought to identify factors that might control heterochromatin at DXZ4. In human embryonic stem cells, we found low levels of 5-hydroxymethylcytosine at DXZ4 and that this mark is lost upon differentiation as H3K9me3 is acquired. We identified two previously undescribed DXZ4 associated noncoding transcripts (DANT1 and DANT2) that are transcribed toward DXZ4 from promoters flanking the array. Each generates transcript isoforms that traverse the MSR. However, upon differentiation, enhancer of Zeste-2 silences DANT1, and DANT2 transcription terminates prior to entering DXZ4. These data support a model wherein DANT1 and/or DANT2 may function to regulate constitutive heterochromatin formation at this MSR.
authors.affiliation: Department of Biological Science, Florida State University, 319 Stadium Drive, King 3076, Tallahassee, FL, 32306-4295, USA.|NHLBI, National Institutes of Health, 10 center Drive, Building 10 Rm 6D12, Bethesda, MD, 20892, USA.
authors.forename: Debbie M
authors.initials: DM
authors.lastname: Figueroa
authors.affiliation: Department of Biological Science, Florida State University, 319 Stadium Drive, King 3076, Tallahassee, FL, 32306-4295, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Darrow
authors.affiliation: Department of Biological Science, Florida State University, 319 Stadium Drive, King 3076, Tallahassee, FL, 32306-4295, USA. chadwick@bio.fsu.edu.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Chadwick
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D002461:Cell Line, Transformed; D042002:Chromatin Assembly and Disassembly; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X; D019175:DNA Methylation; D004276:DNA, Satellite; D005260:Female; D015870:Gene Expression; D006570:Heterochromatin / Q000235:genetics*; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics*; D015203:Reproducibility of Results; D049951:X Chromosome Inactivation
chemical_list: D004276:DNA, Satellite; D006570:Heterochromatin; D062085:RNA, Long Noncoding
keywords: DXZ4; Euchromatin and heterochromatin; Human embryonic stem cells; Long noncoding RNA; Macrosatellite; X chromosome inactivation