Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Acss2 Deletion Reveals Functional Versatility via Tissue-Specific Roles in Transcriptional Regulation

Narayanan Puthillathu Vasudevan
,
Dharmendra K. Soni
ORCID logo ,
John R. Moffett
ORCID logo ,
Jishnu K.S. Krishnan
ORCID logo ,
Abhilash P. Appu
,
Sarani Ghoshal
,
Peethambaran Arun
,
John M. Denu
,
Thomas P. Flagg
ORCID logo ,
Roopa Biswas
ORCID logo ,
Aryan M. Namboodiri
*
Version 1 : Received: 17 January 2023 / Approved: 19 January 2023 / Online: 19 January 2023 (01:40:55 CET)

A peer-reviewed article of this Preprint also exists.

Vasudevan, N.P.; Soni, D.K.; Moffett, J.R.; Krishnan, J.K.S.; Appu, A.P.; Ghoshal, S.; Arun, P.; Denu, J.M.; Flagg, T.P.; Biswas, R.; Namboodiri, A.M. Acss2 Deletion Reveals Functional Versatility via Tissue-Specific Roles in Transcriptional Regulation. Int. J. Mol. Sci. 2023, 24, 3673. Vasudevan, N.P.; Soni, D.K.; Moffett, J.R.; Krishnan, J.K.S.; Appu, A.P.; Ghoshal, S.; Arun, P.; Denu, J.M.; Flagg, T.P.; Biswas, R.; Namboodiri, A.M. Acss2 Deletion Reveals Functional Versatility via Tissue-Specific Roles in Transcriptional Regulation. Int. J. Mol. Sci. 2023, 24, 3673.

Abstract

Coordination of cellular biological processes is regulated in part via metabolic enzymes acting to match cellular metabolism to current conditions. The acetate activating enzyme, acyl-coenzyme A synthetase short-chain family member 2 (Acss2) has long been considered to have a predominantly lipogenic function. More recent evidence suggests that this enzyme has regulatory functions in addition to its role in providing acetyl-CoA for lipid synthesis. We used Acss2 knockout mice (Acss2-/-) to further investigate the roles this enzyme plays in three physiologically distinct organ systems that make extensive use of lipid synthesis and storage including the liver, brain and adipose tissue. We examined the resulting transcriptomic changes resulting from Acss2 deletion and assessed these changes in relation to fatty acid constitution. We find that loss of Acss2 leads to dysregulation of numerous canonical signaling pathways, upstream transcriptional regulatory molecules, cellular processes, and biological functions, which were distinct in the liver, brain and mesenteric adipose tissues. The detected organ-specific transcriptional regulatory patterns reflect the complementary functional roles of these organ systems within the context of systemic physiology. While alterations in transcriptional states were evident, the loss of Acss2 resulted in few changes in fatty acid constitution in all three organ systems. Overall, we demonstrate Acss2 loss institutes organ-specific transcriptional regulatory patterns reflecting the complementary functional roles of these organ systems. Collectively, these findings provide further confirmation that Acss2 regulates key transcription factors and pathways under well-fed, non-stressed conditions, and acts as a transcriptional regulatory enzyme.

Keywords

acetate; acetyl-coenzyme A; ATP citrate lyase; acetyl-CoA synthetase; acetylation; transcriptional regulation

Subject

Biology and Life Sciences, Anatomy and Physiology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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