Epigenetic memory in induced pluripotent stem cells
Authors: R A Irizarry
R Weissleder
A Doi
R Zhao
K Kim
S H Orkin
A Yabuuchi
J Seita
R Jaenisch
M J Aryee
L I R Ehrlich
K C Cunniff
P Cahan
S McKinney-Freeman
B Wen
T J Yoon
K Ng
N Jung
J Kim
A Takeuchi
G Q Daley
A P Feinberg
J Hanna
H Ji
H Hongguang
P Murakami
O Naveiras
I L Weissman
Journal: Nature (2010)
Discipline: Multidisciplinary
Keywords: Somatic cell nuclear transfer; transcription-factor-based reprogramming; pluripotent stem cells; genomic methylation; epigenetic modification
Affiliations: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA

Abstract:  Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment. 

Retracted: No

PubPeer comments:
 Fig 6. ![file] The tumors also appear, differently identified, in [Sun, Lv Zhang (2020)] and [Zhang et al (2020)] . ![] , 
 Comparing Fig 6C (right) with Fig 8C [left] from [Gao et al (2017)] . ![file] Could the authors clarify whether the bottom right panel is stained for p-JNK-1 2 or Cleaved PARP? , 
 Middle: Fig 2B :  Effects of hispidulin on cell metastatic ability. ... B: Transwell invasion assay analyzed cell invasion in Caki-2 and A498 cells after treatment with hispidulin (10 u00b5M or 20 u00b5M). Above: Fig. 6F from [Pan et al (2018)] :  Physcion induces autophagy in the HCC cells by inactivating the JAK2 STAT3 pathway. ... (F) Cell migration and invasion abilities assayed by wound healing and Transwell invasion protocols. Bottom: Figs 2E ( MiR-137 restrains cell invasion ) and 3E ( Anti-miR-137 stimulates cell invasion ) from [Wang et al (20198)] . ![file] Duplicated panels marked. , 
 Retracted 1 June 2020. https: www.ncbi.nlm.nih.gov pmc articles PMC7339277  Falsified materials and or data reported in this publication had been detected by a knowledgeable reader and subsequently confirmed by further investigation of editorial office. Therefore, the entire article has been retracted in accordance with this journalu2019s policy and Editorial decision. , 
 Google Scholar informs us that this retracted fabrication has been cited in 23 papers, to date. Many of those are lazy uncritical  literature reviews , but nine are problematic enough to have their own Pubpeer threads: - [Liu et al (2018)] - retracted. - [Han et al (2018)] . - [Han et al (2019)] . - [Z. Li et al (2019)] - retracted. - [D. Li et al (2019)] . - [Zhao, Xu Lv (2019)] - retracted. - [Wang et al (2019)] - retracted. - [Gao et al (2020)] . - [Wei et al (2019)] . One possible explanation for this self-citing parallel-universe literature is that many papers with ostensibly different authorship are the products of a papermill, citing their own previous products (sold to different customers). ,