Gene transcription is governed by the posttranslational modification of histones that recruit the effectors of gene transcription. The posttranslational modification of histones can result in short-term control of gene transcription o they can act as long-term epigenetic determinants of gene transcription that can faithfully transmit the activation status of a gene across many cellular generations. A recent large-scale exome screen identified a mutation in the gene UBR7 in a family with autism. UBR7 contains a UBR- box and therefore belongs to a family of proteins involved in the recognition and ubiquitination of proteins that contain an N-degron signal sequence. UBR7 is the most divergent of the seven family members and has no demonstrated affinity for N-degron containing proteins. UBR7 also contains a PHD domain immediately adjacent to the UBR-box which makes it unique from other UBR proteins. PHD domains are common in chromatin associated protein that binds to posttranslationally modified histone H3 amino terminal tails. The function of UBR7 and it role in autism are completely undefined. We hypothesize that UBR7 binds chromatin via its PHD domain and regulates transcription through ubiquitination of histone proteins. The mutation associated with autism lies between the UBR-Box and PHD domains. We expect that the autism-associated mutant will alter the function of the UBR-box, PHD domain or both, and result in altered gene expression that contributes to the development of autism. The experiments proposed with test the binding of UBR7 to modified histone H3 amino terminal tails, assess the E3 ligase activity of UBR7 and determine if the autism associated mutant affects these properties. We determine the genes regulated by UBR7 and compare their expression between cells containing wild-type and mutated UBR7. Together these experiments will provide the first mechanistic description of a new autism gene and characterize a unique chromatin associated protein that may couple posttranslational modification of histones to ubiquitinylation.

Public Health Relevance

Unique patterns of histone posttranslational modification control gene regulation by the selective recruitment of effector protein complexes. Histone readers are the proteins that bind to modified histone tails. Recently, a mutation in the protein UBR7, which we propose as a novel histone reader, was identified in a family with autism. Our proposal addresses the hypothesis that UBR7 regulates gene transcription by binding histones, and the mutation in UBR7 found in individuals with autism causes a disregulation of the mechanism by which the protein recognizes its gene targets or exerts its function. Autism is a heritable disorder but its etiology and presentation are highly heterogeneous. Understanding the normal function of genes related to autism as well as the impact of disease related mutations is crucial to understanding this heterogeneous disease, and to identify potential therapeutic approaches. These studies have will identify a completely new pathway involved in the etiology of autism and provide the first description of the function of UBR7.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD078946-01A1
Application #
8770744
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Parisi, Melissa
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904