ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons.

Abstract

ATRX (the alpha thalassemia/mental retardation syndrome X-linked protein) is a member of the switch2/sucrose nonfermentable2 (SWI2/SNF2) family of chromatin-remodeling proteins and primarily functions at heterochromatic loci via its recognition of "repressive" histone modifications [e.g., histone H3 lysine 9 tri-methylation (H3K9me3)]. Despite significant roles for ATRX during normal neural development, as well as its relationship to human disease, ATRX function in the central nervous system is not well understood. Here, we describe ATRX's ability to recognize an activity-dependent combinatorial histone modification, histone H3 lysine 9 tri-methylation/serine 10 phosphorylation (H3K9me3S10ph), in postmitotic neurons. In neurons, this "methyl/phos" switch occurs exclusively after periods of stimulation and is highly enriched at heterochromatic repeats associated with centromeres. Using a multifaceted approach, we reveal that H3K9me3S10ph-bound Atrx represses noncoding transcription of centromeric minor satellite sequences during instances of heightened activity. Our results indicate an essential interaction between ATRX and a previously uncharacterized histone modification in the central nervous system and suggest a potential role for abnormal repetitive element transcription in pathological states manifested by ATRX dysfunction.

• Authors: Kyung-Min Noh, Ian Maze, Dan Zhao, Bin Xiang, Wendy Wenderski, Peter W Lewis, Li Shen, Haitao Li, C David Allis
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 22 Pg. 6820-7 (Jun 02 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25538301 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Histones
• Nuclear Proteins
• DNA Helicases
• ATRX protein, human
• X-linked Nuclear Protein

Topics

• Animals
• Calorimetry
• Chromatin Immunoprecipitation
• Crystallization
• DNA Helicases (metabolism)
• DNA Methylation (physiology)
• DNA Primers (genetics)
• Drosophila
• Female
• Flow Cytometry
• Fluorescent Antibody Technique
• Gene Silencing
• Histones (metabolism)
• Humans
• Image Processing, Computer-Assisted
• Mice
• Mice, Inbred C57BL
• Neurons (metabolism)
• Nuclear Proteins (metabolism)
• Pregnancy
• Repetitive Sequences, Nucleic Acid (physiology)
• X-linked Nuclear Protein