CREB-mediated transcriptional activation of NRMT1 drives muscle differentiation

Tooley, John G.; Catlin, James; Tooley, Christine E. Schaner

doi:10.1080/21541264.2021.1963627

Cited by 11 publications

(15 citation statements)

References 69 publications

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“…The closest sequence homolog to NRMT1, NRMT2 (also known as METTL11B), is an Nα-monomethylase, and its transcript levels have been shown to increase during osteocytic and myogenic differentiation [50]. We have seen a similar upregulation of NRMT1 transcript levels during myogenic differentiation [51].…”

Section: Discussionsupporting

confidence: 60%

Age-related neurodegeneration and cognitive impairments of NRMT1 knockout mice are preceded by misregulation of RB and abnormal neural stem cell development

et al. 2021

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N-terminal methylation is an important posttranslational modification that regulates protein/DNA interactions and plays a role in many cellular processes, including DNA damage repair, mitosis, and transcriptional regulation. Our generation of a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 demonstrated its loss results in severe developmental abnormalities and premature aging phenotypes. As premature aging is often accompanied by neurodegeneration, we more specifically examined how NRMT1 loss affects neural pathology and cognitive behaviors. Here we find that Nrmt1−/− mice exhibit postnatal enlargement of the lateral ventricles, age-dependent striatal and hippocampal neurodegeneration, memory impairments, and hyperactivity. These morphological and behavior abnormalities are preceded by alterations in neural stem cell (NSC) development. Early expansion and differentiation of the quiescent NSC pool in Nrmt1−/− mice is followed by its subsequent depletion and many of the resulting neurons remain in the cell cycle and ultimately undergo apoptosis. These cell cycle phenotypes are reminiscent to those seen with loss of the NRMT1 target retinoblastoma protein (RB). Accordingly, we find misregulation of RB phosphorylation and degradation in Nrmt1−/− mice, and significant de-repression of RB target genes involved in cell cycle. We also identify novel de-repression of Noxa, an RB target gene that promotes apoptosis. These data identify Nα-methylation as a novel regulatory modification of RB transcriptional repression during neurogenesis and indicate that NRMT1 and RB work together to promote NSC quiescence and prevent neuronal apoptosis.

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Section: Discussionsupporting

confidence: 60%

Age-related neurodegeneration and cognitive impairments of NRMT1 knockout mice are preceded by misregulation of RB and abnormal neural stem cell development

et al. 2021

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“…1 H NMR (500 MHz, CDCl 3 ): δ 6.34 (s, 1H), 6.25 (s, 1H), 4.86 (s, 1H), 3.97 (s, 1H), 3.52 (dd, J = 14.1, 8.4 Hz, 1H), 3.30 (t, J = 7.9 Hz, 2H), 3.20 (q, J = 10.5 Hz, 3H), 3.02 (s, 3H), 2.33 (s, 1H), 2.23 (s, 1H), 1.99 (dt, J = 7.5, 3.5 Hz, 1H), 1.87−1.70 (m, 2H), 1.62 (s, 6H). 13 (19). Compound 19 (650 mg, yield 61%) was prepared with the same synthetic method as 1.…”

Section: (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)prop...mentioning

confidence: 99%

“…18 Loss of NTMT1 in C2C12 mouse myoblasts leads to expression of osteogenic markers. 19 However, the detailed mechanisms and pathways regulated by NTMT1 are not yet completely understood. In this regard, highly cell-active and specific inhibitors would be valuable to probe the physiological and pharmacological functions of NTMT1/2.…”

Section: Introductionmentioning

confidence: 99%

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Structure–Activity Relationship Studies of Venglustat on NTMT1 Inhibition

et al. 2023

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The protein N-terminal methyltransferase 1 (NTMT1) is implicated in neurogenesis, retinoblastoma, and cervical cancer. However, its pharmacological potentials have not been elucidated due to the lack of drug-like inhibitors. Here, we report the discovery of the first NTMT1 in vivo chemical probe GD433 by structure-guided optimization of our previously reported lead compound venglustat. GD433 (IC50 = 27 ± 1.1 nM) displays improved potency and selectivity than venglustat across biochemical, biophysical, and cellular assays. GD433 also displays good oral bioavailability and can serve as an in vivo chemical probe to dissect the pharmacological roles of Nα methylation. In addition, we also identified a close analogue (YD2160) that is inactive against NTMT1. The active inhibitor and negative control will serve as valuable tools to examine the physiological and pharmacological functions of NTMT1 catalytic activity.

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“…Our lab and others have identified many downstream effects of the loss of METTL11A, including impaired DNA damage repair, altered cell proliferation, abnormal muscle cell differentiation, and premature neural stem cell depletion ( 6 , 7 , 8 , 9 ). METTL11A acts as a tumor suppressor in breast cancer cells, as its knockdown promotes DNA damage, cell proliferation, invasive potential, and xenograft tumor growth ( 6 ).…”

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confidence: 99%