An AUTS2–Polycomb complex activates gene expression in the CNS

Abstract

SummaryNaturally occurring variations of Polycomb Repressive Complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, Autism Susceptibility Candidate 2 (AUTS2). While AUTS2 is often disrupted in patients with neuronal disorders, the underlying mechanism is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrated that the CK2 component of PRC1-AUTS2 thwarts PRC1 repressive activity while AUTS2-mediated recruitment of P300 leads to gene activation. ChIP-seq demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.

BMI1–RING1B is an autoinhibited RING E3 ubiquitin ligase

“…It remains to be determined in detail how other PRC1 complex components, or regulatory mechanisms such as activating phosphorylation of PCGF proteins 53,54 or inactivating phosphorylation of RING1B within PRC1.5 (ref. 55), influence E3 ligase activity of canonical and non-canonical PRC1.…”

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

“…The CK2 subunit of the complex neutralizes PRC1 repressing activity and subsequent recruitment of P300 by AUTS2 leads to neural gene activation [313]. Similar activating function of PRC1s was described in spermatogenesis.…”

“…Notably, at molecular level, the H2AK119ub1 levels of the Pcgf5 null mutants were reduced in comparison to the control but this reduction had no effect on global gene expression. Genome-wide studies suggested that PRC1.5 complexes encompassing CK2 and AUTS2 are recruited to active genes, uncovering a new function of the PRC1.5 in activating transcription ( [313] and see below). [148,306,307,310] CK2 belongs to the serine/threonine-selective protein kinase family.…”

“…However, the Auts2 gene is deleted conditionally in neuronal progenitor cells by the Cre transgenic Nestin promoter [313]. The mutation was named as Auts2 tm1.1Dare or Tg(Nes-Cre)1Kln/0 where exon 7 of the Auts2 gene is deleted by the Cre transgenic Nestin promoter.…”

A low‐grade astrocytoma in a sixteen‐year‐old boy with a 7q11.22 deletion

“…In this way, AUTS2 plays a role in regulation of neuronal gene expression through promoter association. Their hypothesis is that changes in AUTS2 result in reduced neuronal gene expression trough the AUTS2 ‐PRC1 complex and can give different developmental defects 10. Polycomb group proteins play an important role in neurodevelopment, but deregulation can lead to oncogenesis.…”