A noncoding RNA modulator potentiates phenylalanine metabolism in mice
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A noncoding RNA modulator potentiates phenylalanine metabolism in mice. / Li, Yajuan; Tan, Zhi; Zhang, Yaohua; Zhang, Zhao; Hu, Qingsong; Liang, Ke; Jun, Yao; Ye, Youqiong; Li, Yi-Chuan; Li, Chunlai; Liao, Lan; Xu, Jianming; Xing, Zhen; Pan, Yinghong; Chatterjee, Sujash S; Nguyen, Tina K; Hsiao, Heidi; Egranov, Sergey D; Putluri, Nagireddy; Coarfa, Cristian; Hawke, David H; Gunaratne, Preethi H; Tsai, Kuang-Lei; Han, Leng; Hung, Mien-Chie; Calin, George A; Namour, Fares; Guéant, Jean-Louis; Muntau, Ania C; Blau, Nenad; Sutton, V Reid; Schiff, Manuel; Feillet, François; Zhang, Shuxing; Lin, Chunru; Yang, Liuqing.
in: SCIENCE, Jahrgang 373, Nr. 6555, 06.08.2021, S. 662-673.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A noncoding RNA modulator potentiates phenylalanine metabolism in mice
AU - Li, Yajuan
AU - Tan, Zhi
AU - Zhang, Yaohua
AU - Zhang, Zhao
AU - Hu, Qingsong
AU - Liang, Ke
AU - Jun, Yao
AU - Ye, Youqiong
AU - Li, Yi-Chuan
AU - Li, Chunlai
AU - Liao, Lan
AU - Xu, Jianming
AU - Xing, Zhen
AU - Pan, Yinghong
AU - Chatterjee, Sujash S
AU - Nguyen, Tina K
AU - Hsiao, Heidi
AU - Egranov, Sergey D
AU - Putluri, Nagireddy
AU - Coarfa, Cristian
AU - Hawke, David H
AU - Gunaratne, Preethi H
AU - Tsai, Kuang-Lei
AU - Han, Leng
AU - Hung, Mien-Chie
AU - Calin, George A
AU - Namour, Fares
AU - Guéant, Jean-Louis
AU - Muntau, Ania C
AU - Blau, Nenad
AU - Sutton, V Reid
AU - Schiff, Manuel
AU - Feillet, François
AU - Zhang, Shuxing
AU - Lin, Chunru
AU - Yang, Liuqing
N1 - Copyright © 2021, American Association for the Advancement of Science.
PY - 2021/8/6
Y1 - 2021/8/6
N2 - The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair -/- and Pah R408W/R408W mice and improved the Phe tolerance of these mice.
AB - The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair -/- and Pah R408W/R408W mice and improved the Phe tolerance of these mice.
U2 - 10.1126/science.aba4991
DO - 10.1126/science.aba4991
M3 - SCORING: Journal article
C2 - 34353949
VL - 373
SP - 662
EP - 673
JO - SCIENCE
JF - SCIENCE
SN - 0036-8075
IS - 6555
ER -