Neuronal SETD2 activity links microtubule methylation to an anxiety-like phenotype in mice
Abstract
Gene discovery efforts in autism spectrum disorder have identified heterozygous defects in chromatin remodeller genes, the ‘readers, writers and erasers’ of methyl marks on chromatin, as major contributors to this disease. Despite this advance, a convergent aetiology between these defects and aberrant chromatin architecture or gene expression has remained elusive. Recently, data have begun to emerge that chromatin remodellers also function directly on the cytoskeleton. Strongly associated with autism spectrum disorder, the SETD2 histone methyltransferase for example, has now been shown to directly methylate microtubules of the mitotic spindle. However, whether microtubule methylation occurs in post-mitotic cells, for example on the neuronal cytoskeleton, is not known. We found the SETD2 α-tubulin lysine 40 trimethyl mark occurs on microtubules in the brain and in primary neurons in culture, and that the SETD2 C-terminal SRI domain is required for binding and methylation of α-tubulin. A CRISPR knock-in of a pathogenic SRI domain mutation (Setd2SRI) that disables microtubule methylation revealed at least one wild-type allele was required in mice for survival, and while viable, heterozygous Setd2SRI/wtmice exhibited an anxiety-like phenotype. Finally, whereas RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) showed no concomitant changes in chromatin methylation or gene expression in Setd2SRI/wtmice, primary neurons exhibited structural deficits in axon length and dendritic arborization. These data provide the first demonstration that microtubules of neurons are methylated, and reveals a heterozygous chromatin remodeller defect that specifically disables microtubule methylation is sufficient to drive an autism-associated phenotype.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 20, 2021
- Source ID
- 10.1093/brain/awab200
Entities
People
- Brian Thomas Kalish
- Cheryl Lyn Walker
- Christopher Scott Ward
- Cristian Coarfa
- Durga Nand Tripathi
- In Young Park
- Kristen J. Verhey
- Matthew Neil Rasband
- Matthias Koenning
- Menuka Karki
- Michael A Cianfrocco
- Rahul Kumar Jangid
- Ricardo Mostany
- Ruhee Dere
- Sandra L. Grimm
- Sarah Kearns
- Sung Yun Jung
- W. Kimryn Rathmell
- Xianlong Wang
Organizations
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- Harvard Medical School
- John Templeton Foundation
- National Institutes of Health
- Tulane University of Louisiana
- United States Department of Defense
- University of Michigan
- Vanderbilt University