Abstract
Simple SummaryThe coupling of metabolism with cellular status is critically important and highly evolutionarily conserved. However, how cells coordinate metabolism with transcription as they change their status is not clear. Utilizing multiomic and functional studies, we now demonstrate the dichotomous roles of the Kat3 coactivators CBP and p300 and, in particular, their extreme N-termini, in coordinating cellular metabolism with cell differentiation. Using multiple in vitro and in vivo systems, our study sheds new light on metabolic regulation in homeostasis and disease, including cancer.The integration of cellular status with metabolism is critically important and the coupling of energy production and cellular function is highly evolutionarily conserved. This has been demonstrated in stem cell biology, organismal, cellular and tissue differentiation and in immune cell biology. However, a molecular mechanism delineating how cells coordinate and couple metabolism with transcription as they navigate quiescence, growth, proliferation, differentiation and migration remains in its infancy. The extreme N-termini of the Kat3 coactivator family members, CBP and p300, by far the least homologous regions with only 66% identity, interact with members of the nuclear receptor family, interferon activated Stat1 and transcriptionally competent β-catenin, a critical component of the Wnt signaling pathway. We now wish to report based on multiomic and functional investigations, utilizing p300 knockdown, N-terminal p300 edited and p300 S89A edited cell lines and p300 S89A knockin mice, that the N-termini of the Kat3 coactivators provide a highly evolutionarily conserved hub to integrate multiple signaling cascades to coordinate cellular metabolism with the regulation of cellular status and function.
Highlights
The integration of a cell’s state with its metabolism is critically important and the coupling of energy production and cellular function is highly evolutionarily conserved.This has been demonstrated in stem cell biology, organismal, cellular and tissue differentiation and, perhaps most extensively, in immune cell biology [1–3]
EDITED cells were generated by deletion of 9aa in exon 2 of p300, which plays a critical role in controlling crosstalk between the nuclear receptor family and the Wnt signaling cascade and the initiation of a feed-forward differentiation mechanism [30]
P19 EDITED cells treated with all-trans retinoic acid (ATRA) displayed significantly enhanced expression of the key glycolytic enzymes Aldoa, Aldoc, Eno1, Eno2 and Pgam1 compared to the wild type ATRA treated P19 cells, as judged by qPCR
Summary
The integration of a cell’s state with its metabolism is critically important and the coupling of energy production and cellular function is highly evolutionarily conserved. This has been demonstrated in stem cell biology, organismal, cellular and tissue differentiation and, perhaps most extensively, in immune cell biology [1–3]. The Wnt signaling cascade plays a significant role in the maintenance, proliferation and differentiation of stem/progenitor cells [4–6] as well as in regulating multiple metabolic parameters, including glucose metabolism, de novo lipogenesis and mitochondrial physiology [7,8]. A very recent report outlined the critical role of several nuclear receptors, including PPAR-α and ESRRA, in proximal tubule kidney cells, via coordination of metabolism and differentiation and their dysfunction in kidney fibrosis [11]. Numerous studies have documented a significant profibrotic role for aldosterone, via the mineralocorticoid receptor, in the progression of chronic kidney disease [12,13]
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