Networking shapes our brains in many ways; whether it be in a professional, social, or genomically imprinted fashion. Linking us into the latter, new findings from the lab of Janine LaSalle at the University of California, Davis, uncover a hub in an imprinted gene network critical to neurodevelopment.
The imprinted 15q11-q13 locus is involved in neurodevelopmental disorders such as Angelman, Prader-Willi, and Dup15q syndromes. Dup15q is an autism spectrum disorder (ASD) with a known genetic cause. Within the complex 15q11-q13 locus lies Ube3a, a ubiquitin ligase that is maternally expressed in neurons. Ube3a targets Ring1b, another ubiquitin ligase that is a member of the polycomb repressive 1 complex (PRC1), which monoubiquitinates the histone variant H2A.Z. Previously, the LaSalle lab has demonstrated that post-mortem Dup15q brains and a Dup15q cell culture exhibit global DNA hypomethylation and altered H2A.Z positioing at genes used for neuronal signaling, which are also ASD candidate genes.
To dig deeper into the epigenomic functions of Ube3a, the talented team employed siRNA to knockdown Ube3a in a human neuroblastoma cell line (SH-SY5Y) and a Dup15q model cell line known as SH(15M). Here’s what they discovered when they applied whole-genome bisulfite sequencing, ChIP-seq, and RNA-seq to examine DNA methylation, H2A.Z & H3K4me3, and gene expression:
- DNA methylation, H2A.Z positioning, and H3K4me3 maintain a tight relationship following alterations to Ube3a; however, altered transcription does not typically reflect epigenomic differences.
- The team hypothesizes that the epigenomic differences represent a fingerprint of past developmental events, while the transcriptional changes are transient
- Either a gain or loss of Ube3a alters DNA methylation at genes involved in neurodevelopment and transcriptional regulation, which are associated with ASD related behaviors
- Knockdown of Ube3a alters the methylation of half of all known imprinted genes, thus uncovering an imprinted gene network in the brain associated with ASD
First author S. Jesse Lopez shares, “I would say that imprinted gene networks are yet another layer of regulation in neurodevelopment. Imprinting is a complex epigenetic process where certain genes are turned on and off at different developmental stages and even different brain regions and the idea that they are controlled in networks highlights the delicate balance of brain development.”
Senior author Janine LaSalle concludes, “Imprinted genes and imprinted human neurodevelopmental disorders such as Angelman syndrome were what originally got me interested in epigenetic mechanisms back in the 90’s in my postdoc years. But I was surprised to see that imprinted genes were selectively enriched in this unbiased analysis of the transcriptome and epigenome in human neurons when UBE3A levels were altered. Clearly, we have more work to do to further understand the implications of an imprinted gene network in neurons mediated by UBE3A and the relevance of other imprinted genes to autism.”
Go peel away at the layers of this network over at Epigenetics, September 2017