Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line

Lucy Lin, Mavis R. Swerdel, Michael P. Lazaropoulos, Gary S. Hoffman, Alana J. Toro-Ramos, Jennifer Wright, Howard Lederman, Jianmin Chen, Jennifer C. Moore, Ronald Hart

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

A spontaneously reverted iPSC line was identified from an A-T subject with heterozygous ATM truncation mutations. The reverted iPSC line expressed ATM protein and was capable of radiation-induced phosphorylation of CHK2 and H2A.X. Genome-wide SNP analysis confirmed a match to source T cells and also to a distinct, non-reverted iPSC line from the same subject. Rearranged T cell receptor sequences predict that the iPSC culture originated as several independently reprogrammed cells that resolved into a single major clone, suggesting that gene correction likely occurred early in the reprogramming process. Gene expression analysis comparing ATM-/- iPSC lines to unrelated ATM+/- cells identifies a large number of differences, but comparing only the isogenic pair of A-T iPSC lines reveals that the primary pathway affected by loss of ATM is a diminished expression of p53-related mRNAs. Gene reversion in culture, although likely a rare event, provided a novel, reverted cell line for studying ATM function.

Original languageEnglish (US)
Pages (from-to)1097-1108
Number of pages12
JournalStem Cell Reports
Volume5
Issue number6
DOIs
StatePublished - Dec 8 2015

Fingerprint

Automatic teller machines
Genes
Ataxia Telangiectasia Mutated Proteins
Cells
Cell Line
T-Cell Antigen Receptor
Single Nucleotide Polymorphism
Clone Cells
Phosphorylation
Genome
Radiation
T-Lymphocytes
Gene Expression
Messenger RNA
Mutation
T-cells
Cell culture
Gene expression

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Lin, L., Swerdel, M. R., Lazaropoulos, M. P., Hoffman, G. S., Toro-Ramos, A. J., Wright, J., ... Hart, R. (2015). Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line. Stem Cell Reports, 5(6), 1097-1108. https://doi.org/10.1016/j.stemcr.2015.10.010
Lin, Lucy ; Swerdel, Mavis R. ; Lazaropoulos, Michael P. ; Hoffman, Gary S. ; Toro-Ramos, Alana J. ; Wright, Jennifer ; Lederman, Howard ; Chen, Jianmin ; Moore, Jennifer C. ; Hart, Ronald. / Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line. In: Stem Cell Reports. 2015 ; Vol. 5, No. 6. pp. 1097-1108.
@article{81dea6c4b1b0406eb47967132e09cab8,
title = "Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line",
abstract = "A spontaneously reverted iPSC line was identified from an A-T subject with heterozygous ATM truncation mutations. The reverted iPSC line expressed ATM protein and was capable of radiation-induced phosphorylation of CHK2 and H2A.X. Genome-wide SNP analysis confirmed a match to source T cells and also to a distinct, non-reverted iPSC line from the same subject. Rearranged T cell receptor sequences predict that the iPSC culture originated as several independently reprogrammed cells that resolved into a single major clone, suggesting that gene correction likely occurred early in the reprogramming process. Gene expression analysis comparing ATM-/- iPSC lines to unrelated ATM+/- cells identifies a large number of differences, but comparing only the isogenic pair of A-T iPSC lines reveals that the primary pathway affected by loss of ATM is a diminished expression of p53-related mRNAs. Gene reversion in culture, although likely a rare event, provided a novel, reverted cell line for studying ATM function.",
author = "Lucy Lin and Swerdel, {Mavis R.} and Lazaropoulos, {Michael P.} and Hoffman, {Gary S.} and Toro-Ramos, {Alana J.} and Jennifer Wright and Howard Lederman and Jianmin Chen and Moore, {Jennifer C.} and Ronald Hart",
year = "2015",
month = "12",
day = "8",
doi = "10.1016/j.stemcr.2015.10.010",
language = "English (US)",
volume = "5",
pages = "1097--1108",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "6",

}

Lin, L, Swerdel, MR, Lazaropoulos, MP, Hoffman, GS, Toro-Ramos, AJ, Wright, J, Lederman, H, Chen, J, Moore, JC & Hart, R 2015, 'Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line', Stem Cell Reports, vol. 5, no. 6, pp. 1097-1108. https://doi.org/10.1016/j.stemcr.2015.10.010

Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line. / Lin, Lucy; Swerdel, Mavis R.; Lazaropoulos, Michael P.; Hoffman, Gary S.; Toro-Ramos, Alana J.; Wright, Jennifer; Lederman, Howard; Chen, Jianmin; Moore, Jennifer C.; Hart, Ronald.

In: Stem Cell Reports, Vol. 5, No. 6, 08.12.2015, p. 1097-1108.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line

AU - Lin, Lucy

AU - Swerdel, Mavis R.

AU - Lazaropoulos, Michael P.

AU - Hoffman, Gary S.

AU - Toro-Ramos, Alana J.

AU - Wright, Jennifer

AU - Lederman, Howard

AU - Chen, Jianmin

AU - Moore, Jennifer C.

AU - Hart, Ronald

PY - 2015/12/8

Y1 - 2015/12/8

N2 - A spontaneously reverted iPSC line was identified from an A-T subject with heterozygous ATM truncation mutations. The reverted iPSC line expressed ATM protein and was capable of radiation-induced phosphorylation of CHK2 and H2A.X. Genome-wide SNP analysis confirmed a match to source T cells and also to a distinct, non-reverted iPSC line from the same subject. Rearranged T cell receptor sequences predict that the iPSC culture originated as several independently reprogrammed cells that resolved into a single major clone, suggesting that gene correction likely occurred early in the reprogramming process. Gene expression analysis comparing ATM-/- iPSC lines to unrelated ATM+/- cells identifies a large number of differences, but comparing only the isogenic pair of A-T iPSC lines reveals that the primary pathway affected by loss of ATM is a diminished expression of p53-related mRNAs. Gene reversion in culture, although likely a rare event, provided a novel, reverted cell line for studying ATM function.

AB - A spontaneously reverted iPSC line was identified from an A-T subject with heterozygous ATM truncation mutations. The reverted iPSC line expressed ATM protein and was capable of radiation-induced phosphorylation of CHK2 and H2A.X. Genome-wide SNP analysis confirmed a match to source T cells and also to a distinct, non-reverted iPSC line from the same subject. Rearranged T cell receptor sequences predict that the iPSC culture originated as several independently reprogrammed cells that resolved into a single major clone, suggesting that gene correction likely occurred early in the reprogramming process. Gene expression analysis comparing ATM-/- iPSC lines to unrelated ATM+/- cells identifies a large number of differences, but comparing only the isogenic pair of A-T iPSC lines reveals that the primary pathway affected by loss of ATM is a diminished expression of p53-related mRNAs. Gene reversion in culture, although likely a rare event, provided a novel, reverted cell line for studying ATM function.

UR - http://www.scopus.com/inward/record.url?scp=84949533058&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949533058&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2015.10.010

DO - 10.1016/j.stemcr.2015.10.010

M3 - Article

C2 - 26677768

AN - SCOPUS:84949533058

VL - 5

SP - 1097

EP - 1108

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

IS - 6

ER -

Lin L, Swerdel MR, Lazaropoulos MP, Hoffman GS, Toro-Ramos AJ, Wright J et al. Spontaneous ATM Gene Reversion in A-T iPSC to Produce an Isogenic Cell Line. Stem Cell Reports. 2015 Dec 8;5(6):1097-1108. https://doi.org/10.1016/j.stemcr.2015.10.010