UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons

S. Jesse Lopez, Keith Dunaway, M. Saharul Islam, Charles Mordaunt, Annie Vogel Ciernia, Makiko Meguro-Horike, Shin ichi Horike, David Segal, Janine M LaSalle

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The dysregulation of genes in neurodevelopmental disorders that lead to social and cognitive phenotypes is a complex, multilayered process involving both genetics and epigenetics. Parent-of-origin effects of deletion and duplication of the 15q11-q13 locus leading to Angelman, Prader-Willi, and Dup15q syndromes are due to imprinted genes, including UBE3A, which is maternally expressed exclusively in neurons. UBE3A encodes a ubiquitin E3 ligase protein with multiple downstream targets, including RING1B, which in turn monoubiquitinates histone variant H2A.Z. To understand the impact of neuronal UBE3A levels on epigenome-wide marks of DNA methylation, histone variant H2A.Z positioning, active H3K4me3 promoter marks, and gene expression, we took a multi-layered genomics approach. We performed an siRNA knockdown of UBE3A in two human neuroblastoma cell lines, including parental SH-SY5Y and the SH(15M) model of Dup15q. Genes differentially methylated across cells with differing UBE3A levels were enriched for functions in gene regulation, DNA binding, and brain morphology. Importantly, we found that altering UBE3A levels had a profound epigenetic effect on the methylation levels of up to half of known imprinted genes. Genes with differential H2A.Z peaks in SH(15M) compared to SH-SY5Y were enriched for ubiquitin and protease functions and associated with autism, hypoactivity, and energy expenditure. Together, these results support a genome-wide epigenetic consequence of altered UBE3A levels in neurons and suggest that UBE3A regulates an imprinted gene network involving DNA methylation patterning and H2A.Z deposition.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalEpigenetics
DOIs
StateAccepted/In press - Nov 1 2017

Fingerprint

Neurons
Epigenomics
Genes
DNA Methylation
Histones
Prader-Willi Syndrome
Ubiquitin-Protein Ligases
Gene Regulatory Networks
Autistic Disorder
Ubiquitin
Genomics
Neuroblastoma
Energy Metabolism
Methylation
Small Interfering RNA
Peptide Hydrolases
Genome
Phenotype
Gene Expression
Cell Line

Keywords

  • autism
  • chromatin
  • DNA methylation
  • epigenetic
  • histone modification
  • imprinting

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Lopez, S. J., Dunaway, K., Islam, M. S., Mordaunt, C., Vogel Ciernia, A., Meguro-Horike, M., ... LaSalle, J. M. (Accepted/In press). UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons. Epigenetics, 1-9. https://doi.org/10.1080/15592294.2017.1376151

UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons. / Lopez, S. Jesse; Dunaway, Keith; Islam, M. Saharul; Mordaunt, Charles; Vogel Ciernia, Annie; Meguro-Horike, Makiko; Horike, Shin ichi; Segal, David; LaSalle, Janine M.

In: Epigenetics, 01.11.2017, p. 1-9.

Research output: Contribution to journalArticle

Lopez, SJ, Dunaway, K, Islam, MS, Mordaunt, C, Vogel Ciernia, A, Meguro-Horike, M, Horike, SI, Segal, D & LaSalle, JM 2017, 'UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons', Epigenetics, pp. 1-9. https://doi.org/10.1080/15592294.2017.1376151
Lopez SJ, Dunaway K, Islam MS, Mordaunt C, Vogel Ciernia A, Meguro-Horike M et al. UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons. Epigenetics. 2017 Nov 1;1-9. https://doi.org/10.1080/15592294.2017.1376151
Lopez, S. Jesse ; Dunaway, Keith ; Islam, M. Saharul ; Mordaunt, Charles ; Vogel Ciernia, Annie ; Meguro-Horike, Makiko ; Horike, Shin ichi ; Segal, David ; LaSalle, Janine M. / UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons. In: Epigenetics. 2017 ; pp. 1-9.
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