LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency.
The RNA-binding proteins LIN28A and LIN28B play critical roles in embryonic development, tumorigenesis, and pluripotency, but their exact functions are poorly understood. Here, we show that, like LIN28A, LIN28B can function effectively with NANOG, OCT4, and SOX2 in reprogramming to pluripotency and that reactivation of both endogenous LIN28A and LIN28B loci are required for maximal reprogramming efficiency. In human fibroblasts, LIN28B is activated early during reprogramming, while LIN28A is activated later during the transition to bona fide induced pluripotent stem cells (iPSCs). In murine cells, LIN28A and LIN28B facilitate conversion from naive to primed pluripotency. Proteomic and metabolomic analysis highlighted roles for LIN28 in maintaining the low mitochondrial function associated with primed pluripotency and in regulating one-carbon metabolism, nucleotide metabolism, and histone methylation. LIN28 binds to mRNAs of proteins important for oxidative phosphorylation and modulates protein abundance. Thus, LIN28A and LIN28B play cooperative roles in regulating reprogramming, naive/primed pluripotency, and stem cell metabolism.
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Jin
J
Zhang
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Sutheera
S
Ratanasirintrawoot
Institute for Medical Engineering and Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Sriram
S
Chandrasekaran
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Zhaoting
Z
Wu
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Scott B
SB
Ficarro
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chunxiao
C
Yu
Center for Individualized Medicine and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Christian A
CA
Ross
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Davide
D
Cacchiarelli
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Qing
Q
Xia
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Marc
M
Seligson
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Gen
G
Shinoda
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Wen
W
Xie
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Patrick
P
Cahan
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Longfei
L
Wang
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Shyh-Chang
SC
Ng
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Supisara
S
Tintara
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Cole
C
Trapnell
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Tamer
T
Onder
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Epigenetics and Cell Fates Laboratory, A(∗)STAR Institute of Molecular and Cell Biology, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
Yuin-Han
YH
Loh
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Tarjei
T
Mikkelsen
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Piotr
P
Sliz
Department of Pathology and Laboratory Medicine, Broad Stem Cell Research Center and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Michael A
MA
Teitell
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
John M
JM
Asara
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Jarrod A
JA
Marto
Center for Individualized Medicine and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Hu
H
Li
Institute for Medical Engineering and Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
James J
JJ
Collins
Stem Cell Transplantation Program, Division of Pediatric Hematology Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: george.daley@childrens.harvard.edu.
George Q
GQ
Daley
D000818:Animals; D002244:Carbon / Q000378:metabolism; D065150:Cellular Reprogramming; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D009711:Nucleotides / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D006657:Histones; C516326:LIN28B protein, human; C488352:Lin-28 protein, mouse; C570876:Lin28b protein, mouse; D009711:Nucleotides; D020543:Proteome; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D002244:Carbon