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Regulation of N6-methyladenosine (m6A) deposition by arginine methylation

Award Number: R01GM133850
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Regulation of N6-methyladenosine (m6A) deposition by arginine methylation - Project Summary Abnormal mRNA metabolism (e.g., mRNA translation and decay) is detrimental to cellular function and has emerged as central to the molecular pathogenesis of many human diseases, such as cancer and neurological diseases. These diseases impose a devastating burden on individuals, as well as their families and communities. Unfortunately, treatment options for many remain limited. Thus, it is urgent to understand how mRNA metabolism is regulated under physiological conditions and how its dysregulation causes diseases. Over the past 5 years, studies on mRNA metabolism have revealed critical functions of various chemical modifications in mRNAs, including pseudouridine (Ψ), 5-methylcytosine (m5C), and N6-methyladenosine (m6A), which has led to the emerging field of epitranscriptomics. m6A is the most abundant internal mRNA modification and is present in over 25% of human mRNAs. Genetic knockout studies of the m6A catalyzing enzymes METTL3 and METTL14 have revealed crucial functions of m6A in the regulation of mRNA metabolism in development and neuronal function. The m6A is co-transcriptionally deposited and highly enriched in 3'-untranslated regions (UTRs) and near stop codons. It has been demonstrated that both the level and location of m6A sites on transcripts are critical for defining the functions m6A in mRNA metabolism. However, fundamental questions remain unanswered: how cells control the level and location of m6A deposition in mRNAs and how dysregulation of this process contributes to disease pathogenesis. Our preliminary studies demonstrate that arginine methylation of METTL14 plays a critical role in maintaining the homeostasis of m6A deposition in cells and that an X-linked mental retardation (XLMR)-associated demethylase is involved in the regulation of METTL14 methylation. Based on these findings we hypothesize that the dynamic regulation of METTL14 arginine methylation by RNAPII through the recruitment of a methyltransferase and demethylase plays a critical role in controlling the level and location of m6A deposition and that dysregulation of this pathway underlies the molecular pathogenesis of impaired neuronal function in XLMR. We will 1) define the role of METTL14 arginine methylation in co-transcriptional m6A deposition; 2) determine the molecular mechanism by which METTL14 arginine methylation is regulated; and 3) investigate the impact of dysregulation of METTL14 arginine methylation on neuronal function. The results from our proposed studies will provide conceptual advances by revealing a novel molecular pathway for transcription- coupled regulation of epitranscriptomics. Identifying regulators of this process will have significant impacts on basic, translational, and clinical research of human diseases, in which loss of function of these regulators have been identified.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $579,600 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	5/2/2023	NON-COMPETING CONTINUATION	$369,600
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	5	8/7/2023	SUPPLEMENT FOR EXPANSION	$210,000
														Subtotal = $579,600

Issue Date FY: 2022 ( Subtotal = $369,600 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	4/6/2022	NON-COMPETING CONTINUATION	$332,640
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	7/27/2022	NON-COMPETING CONTINUATION	$36,960
														Subtotal = $369,600

Issue Date FY: 2021 ( Subtotal = $369,600 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	4/8/2021	NON-COMPETING CONTINUATION	$369,600
														Subtotal = $369,600

Issue Date FY: 2020 ( Subtotal = $369,600 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	4/3/2020	NON-COMPETING CONTINUATION	$369,600
														Subtotal = $369,600

Issue Date FY: 2019 ( Subtotal = $369,600 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	7/25/2019	NEW	$369,600
														Subtotal = $369,600

Grand Total All Awards = $2,058,000

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Regulation of N6-methyladenosine (m6A) deposition by arginine methylation

Award Number: R01GM133850

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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