Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation

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Abstract

CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.

Abstract

CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.

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Liquid phase condensation in cell physiology and disease.

Yongdae Shin, Clifford Brangwynne (2017)

Phase transitions are ubiquitous in nonliving matter, and recent discoveries have shown that they also play a key role within living cells. Intracellular liquid-liquid phase separation is thought to drive the formation of condensed liquid-like droplets of protein, RNA, and other biomolecules, which form in the absence of a delimiting membrane. Recent studies have elucidated many aspects of the molecular interactions underlying the formation of these remarkable and ubiquitous droplets and the way in which such interactions dictate their material properties, composition, and phase behavior. Here, we review these exciting developments and highlight key remaining challenges, particularly the ability of liquid condensates to both facilitate and respond to biological function and how their metastability may underlie devastating protein aggregation diseases.

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Coactivator condensation at super-enhancers links phase separation and gene control

Richard Young, Phillip A Sharp, Ann Boija … (2018)

Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here, we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets and MED1-IDR droplets can compartmentalize and concentrate transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in control of key cell identity genes.

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m 6 A enhances the phase separation potential of mRNA

Ryan Ries, Sara Zaccara, Pierre Klein … (2019)

N 6-methyladenosine (m6A) is the most prevalent modified nucleotide in mRNA 1,2 , with ~25% of mRNAs containing at least one m6A. Methylation of mRNA to form m6A is required for diverse cellular and physiological processes 3 . Although the presence of m6A in an mRNA can affect its fate in different ways, it is unclear how m6A directs this process and why the effects of m6A can vary in different cellular contexts. Here we show that the cytosolic m6A-binding proteins, YTHDF1–3, undergo liquid-liquid phase separation (LLPS) in vitro and in cells. This LLPS is markedly enhanced by mRNAs that contain multiple, but not single, m6A residues. Polymethylated mRNAs act as a multivalent scaffold for binding YTHDF proteins, juxtaposing their low-complexity domains, leading to phase separation. The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated compartments, such as P-bodies, stress granules, or neuronal RNA granules. m6A-mRNA is subject to compartment-specific regulation, including reduced mRNA stability and translation. These studies reveal that the number and distribution of m6A sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome. Additionally, these findings indicate that the cellular properties of m6A-modified mRNAs are governed by liquid-liquid phase separation principles.

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Author and article information

Contributors

Fei Lu: lufeisdu2@163.com

Chunyan Ji:

ORCID: http://orcid.org/0000-0003-4438-1768

jichunyan@sdu.edu.cn

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 30 October 2023

Publication date PMC-release: 30 October 2023

Publication date Collection: 2023

Volume: 14

Electronic Location Identifier: 6907

Affiliations

[1 ]Department of Hematology, Qilu Hospital of Shandong University, ( https://ror.org/056ef9489) Jinan, Shandong China

[2 ]Shandong Key Laboratory of Immunohematology, Qilu Hospital of Shandong University, ( https://ror.org/056ef9489) Jinan, Shandong China

[3 ]Department of Critical Care Medicine, Qilu Hospital of Shandong University, ( https://ror.org/056ef9489) Jinan, Shandong China

Author information

Tao Sun http://orcid.org/0000-0001-8757-9737

Xiuhua Su http://orcid.org/0000-0003-3364-928X

Daoxin Ma http://orcid.org/0000-0003-0664-8441

Chunyan Ji http://orcid.org/0000-0003-4438-1768

Article

Publisher ID: 42650

DOI: 10.1038/s41467-023-42650-3

PMC ID: 10616288

SO-VID: 76a9c684-86b9-4fb1-9ca9-d9df4181bddb

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 20 October 2022

Date accepted : 9 October 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82000165

Award Recipient : Chunyan Ji

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Keywords: phosphorylation,epigenetics,acute myeloid leukaemia,mechanisms of disease,drug regulation

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ScienceOpen disciplines: Uncategorized

Keywords: phosphorylation, epigenetics, acute myeloid leukaemia, mechanisms of disease, drug regulation

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation

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Most cited references 66

Liquid phase condensation in cell physiology and disease.

Coactivator condensation at super-enhancers links phase separation and gene control

m 6 A enhances the phase separation potential of mRNA

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