The Chromatin Regulator HMGA1a Undergoes Phase Separation in the Nucleus**

Hongjia Zhu; Masako Narita; Jerelle A. Joseph; Georg Krainer; William E. Arter; Ioana Olan; Kadi L. Saar; Niklas Ermann; Jorge R. Espinosa; Yi Shen; Masami Ando Kuri; Runzhang Qi; Timothy J. Welsh; Rosana Collepardo-Guevara; Masashi Narita; Tuomas P.J. Knowles

doi:10.1002/cbic.202200450

The Chromatin Regulator HMGA1a Undergoes Phase Separation in the Nucleus**

Hongjia Zhu, Masako Narita, Jerelle A. Joseph, Georg Krainer, William E. Arter, Ioana Olan, Kadi L. Saar, Niklas Ermann, Jorge R. Espinosa, Yi Shen, Masami Ando Kuri, Runzhang Qi, Timothy J. Welsh, Rosana Collepardo-Guevara, Masashi Narita, Tuomas P.J. Knowles

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

The protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro. By bringing together machine-leaning modelling, cellular and biophysical experiments and multiscale simulations, we demonstrate that phase separation of HMGA1a is promoted by protein-DNA interactions, and has the potential to be modulated by post-transcriptional effects such as phosphorylation. We further show that the intrinsically disordered C-terminal tail of HMGA1a significantly contributes to its phase separation through electrostatic interactions via AT hooks 2 and 3. Our work sheds light on HMGA1 phase separation as an emergent biophysical factor in regulating chromatin structure.

Original language	English (US)
Article number	e202200450
Journal	ChemBioChem
Volume	24
Issue number	1
DOIs	https://doi.org/10.1002/cbic.202200450
State	Published - Jan 3 2023
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Molecular Biology
Biochemistry
Organic Chemistry

Keywords

HMGA
chromatin regulators
liquid-liquid phase separation
phase diagrams
protein-DNA interactions

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10.1002/cbic.202200450

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Zhu, H., Narita, M., Joseph, J. A., Krainer, G., Arter, W. E., Olan, I., Saar, K. L., Ermann, N., Espinosa, J. R., Shen, Y., Kuri, M. A., Qi, R., Welsh, T. J., Collepardo-Guevara, R., Narita, M., & Knowles, T. P. J. (2023). The Chromatin Regulator HMGA1a Undergoes Phase Separation in the Nucleus**. ChemBioChem, 24(1), Article e202200450. https://doi.org/10.1002/cbic.202200450

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abstract = "The protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro. By bringing together machine-leaning modelling, cellular and biophysical experiments and multiscale simulations, we demonstrate that phase separation of HMGA1a is promoted by protein-DNA interactions, and has the potential to be modulated by post-transcriptional effects such as phosphorylation. We further show that the intrinsically disordered C-terminal tail of HMGA1a significantly contributes to its phase separation through electrostatic interactions via AT hooks 2 and 3. Our work sheds light on HMGA1 phase separation as an emergent biophysical factor in regulating chromatin structure.",

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author = "Hongjia Zhu and Masako Narita and Joseph, {Jerelle A.} and Georg Krainer and Arter, {William E.} and Ioana Olan and Saar, {Kadi L.} and Niklas Ermann and Espinosa, {Jorge R.} and Yi Shen and Kuri, {Masami Ando} and Runzhang Qi and Welsh, {Timothy J.} and Rosana Collepardo-Guevara and Masashi Narita and Knowles, {Tuomas P.J.}",

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AU - Zhu, Hongjia

AU - Narita, Masako

AU - Joseph, Jerelle A.

AU - Krainer, Georg

AU - Arter, William E.

AU - Olan, Ioana

AU - Saar, Kadi L.

AU - Ermann, Niklas

AU - Espinosa, Jorge R.

AU - Shen, Yi

AU - Kuri, Masami Ando

AU - Qi, Runzhang

AU - Welsh, Timothy J.

AU - Collepardo-Guevara, Rosana

AU - Narita, Masashi

AU - Knowles, Tuomas P.J.

PY - 2023/1/3

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N2 - The protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro. By bringing together machine-leaning modelling, cellular and biophysical experiments and multiscale simulations, we demonstrate that phase separation of HMGA1a is promoted by protein-DNA interactions, and has the potential to be modulated by post-transcriptional effects such as phosphorylation. We further show that the intrinsically disordered C-terminal tail of HMGA1a significantly contributes to its phase separation through electrostatic interactions via AT hooks 2 and 3. Our work sheds light on HMGA1 phase separation as an emergent biophysical factor in regulating chromatin structure.

AB - The protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro. By bringing together machine-leaning modelling, cellular and biophysical experiments and multiscale simulations, we demonstrate that phase separation of HMGA1a is promoted by protein-DNA interactions, and has the potential to be modulated by post-transcriptional effects such as phosphorylation. We further show that the intrinsically disordered C-terminal tail of HMGA1a significantly contributes to its phase separation through electrostatic interactions via AT hooks 2 and 3. Our work sheds light on HMGA1 phase separation as an emergent biophysical factor in regulating chromatin structure.

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KW - chromatin regulators

KW - liquid-liquid phase separation

KW - phase diagrams

KW - protein-DNA interactions

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The Chromatin Regulator HMGA1a Undergoes Phase Separation in the Nucleus**

Abstract

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