Department of Biochemistry and Molecular Pharmacology, New York University Langone School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Mol Cell. 2021 Nov 18;81(22):4663-4676.e8. doi: 10.1016/j.molcel.2021.09.020. Epub 2021 Oct 11.
The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.
包含多梳抑制复合物 1（PRC1）的异质家族复合物对于建立转录抑制的兼性异染色质是必不可少的。然而，两种 PRC1 物种，ncPRC1.3 和 ncPRC1.5，已知包含新的成分，AUTS2、P300 和 CK2，将这种抑制功能转化为转录激活功能。在这里，我们报告说，携带 AUTS2 的 HX 重复结构域突变的个体表现出 AUTS2 和 P300 相互作用的缺陷，以及反映 Rubinstein-Taybi 综合征的发育障碍，Rubinstein-Taybi 综合征主要与 CREBBP/EP300 的杂合致病性变异相关。此外，AUTS2 的缺失或其 HX 重复结构域的突变会导致一组发育基因的失调，并限制小鼠胚胎干细胞中运动神经元的分化。转录因子核呼吸因子 1（NRF1）在这个神经发育过程中具有新的和整体的作用，需要 ncPRC1.3 募集到染色质。
