Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Center for Integrative Biology, Université de Toulouse, UPS and CNRS, F-31062 Toulouse, France
Published: February 2016
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Article Abstract
Pericentric heterochromatin is a highly compacted structure required for accurate chromosome segregation in mitosis. In mammals, it relies on methylation of histone H3K9 by Suv39H enzymes, which provides a docking site for HP1 proteins, therefore mediating heterochromatin compaction. Here we show that, when this normal compaction pathway is defective, the histone acetyltransferase Tip60 is recruited to pericentric heterochromatin, where it mediates acetylation of histone H4K12. Furthermore, in such a context, depletion of Tip60 leads to derepression of satellite transcription, decompaction of pericentric heterochromatin, and defects in chromosome segregation in mitosis. Finally, we show that depletion of BRD2, a double bromodomain-containing protein that binds H4K12ac, phenocopies the Tip60 depletion with respect to heterochromatin decompaction and defects in chromosome segregation. Taking the results together, we identify a new compaction pathway of mammalian pericentric heterochromatin relying on Tip60 that might be dependent on BRD2 recruitment by H4K12 acetylation. We propose that the underexpression of Tip60 observed in many human tumors can promote genetic instability via defective pericentric heterochromatin.
Laboratory of Chromosome Engineering, Department of Frontier Research and Development, Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu 292-0818, Japan.
Aneuploidy is caused by chromosomal missegregation and is frequently observed in cancers and hematological diseases. Therefore, it is important to understand the molecular mechanisms underlying chromosomal segregation. The centromere's intricate structure is crucial for proper chromosome segregation, with heterochromatin at the pericentromeric α-satellites playing a key role.
Pericentromeres are heterochromatic regions adjacent to centromeres that ensure accurate chromosome segregation. Despite their conserved function, they are composed of rapidly evolving A/T-rich satellite DNA. This paradoxical observation is partially resolved by epigenetic mechanisms that maintain heterochromatin, independent of specific DNA sequences.
New Cornerstone Science Laboratory, Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430072, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of Epigenetic Regulation and Intervention, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:
Genome differential positioning within interphase nuclei remains poorly explored. We extended and validated Tyramide Signal Amplification (TSA)-seq to map genomic regions near nucleoli and pericentric heterochromatin in four human cell lines. Our study confirmed that smaller chromosomes localize closer to nucleoli but further deconvolved this by revealing a preference for chromosome arms below 36-46 Mbp in length.
Pericentric heterochromatin is a critical component of chromosomes marked by histone H3 K9 (H3K9) methylation. However, what recruits H3K9-specific histone methyltransferases to pericentric regions in vertebrates remains unclear, as does why pericentric regions in different species share the same H3K9 methylation mark despite lacking highly conserved DNA sequences. Here we show that zinc-finger proteins ZNF512 and ZNF512B specifically localize at pericentric regions through direct DNA binding.
