Dynamic nucleolar phase separation influenced by non-canonical function of LIN28A instructs pluripotent stem cell fate decisions

Tianyu Tan, Bo Gao, Hua Yu, Hongru Pan, Zhen Sun, Anhua Lei, Li Zhang, Hengxing Lu, Hao Wu, George Q. Daley, Yu Feng () and Jin Zhang ()
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Tianyu Tan: and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine
Bo Gao: Zhejiang University School of Medicine
Hua Yu: and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine
Hongru Pan: and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine
Zhen Sun: and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine
Anhua Lei: and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine
Li Zhang: and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine
Hengxing Lu: Zhejiang University
Hao Wu: Harvard Medical School
George Q. Daley: Harvard Medical School
Yu Feng: Zhejiang University School of Medicine
Jin Zhang: and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract LIN28A is important in somatic reprogramming and pluripotency regulation. Although previous studies addressed that LIN28A can repress let-7 microRNA maturation in the cytoplasm, few focused on its role within the nucleus. Here, we show that the nucleolus-localized LIN28A protein undergoes liquid-liquid phase separation (LLPS) in mouse embryonic stem cells (mESCs) and in vitro. The RNA binding domains (RBD) and intrinsically disordered regions (IDR) of LIN28A contribute to LIN28A and the other nucleolar proteins’ phase-separated condensate establishment. S120A, S200A and R192G mutations in the IDR result in subcellular mislocalization of LIN28A and abnormal nucleolar phase separation. Moreover, we find that the naive-to-primed pluripotency state conversion and the reprogramming are associated with dynamic nucleolar remodeling, which depends on LIN28A’s phase separation capacity, because the LIN28A IDR point mutations abolish its role in regulating nucleolus and in these cell fate decision processes, and an exogenous IDR rescues it. These findings shed light on the nucleolar function in pluripotent stem cell states and on a non-canonical RNA-independent role of LIN28A in phase separation and cell fate decisions.

Date: 2024
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DOI: 10.1038/s41467-024-45451-4

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