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| Status |
Public on Feb 01, 2016 |
| Title |
Gene expression response to mitochondrial DNA depletion |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Mitochondrial defects are associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as diabetes and neurodegeneration. In lower organisms, genetic “retrograde” signaling programs have been identified that promote cellular and organism survival in the face of mitochondrial dysfunction. Here, we characterized the transcriptional component of the human mitochondrial retrograde response in an inducible model of mitochondrial dysfunction.
We used an HEK293-derived cell line that expresses a dominant negative DNA polymerase gamma (PolGdn) under tet repressor control. Upon induction with doxycycline, PolGdn inhibits replication of mitochondrial DNA (mtDNA), so that existing copies of mtDNA are progressively diluted as cells continue to divide. Upon removal of doxycycline, repression of PolGdn is re-established, and mtDNA copy number, as well as mitochondrial protein expression and oxidative phosphorylation complex abundance, recovers. We used microarrays to study transcriptional changes arising from mtDNA depletion. We found a robust transcriptional response that is partially mediated by ATF4, which appears to effect an adaptive rewiring of serine and one-carbon metabolism.
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| Overall design |
We measured gene expression at 18 different time points during the mtDNA depletion / repletion process, as average mtDNA copy number fell approximately 40-fold and then recovered to baseline. In addition, we performed similar measurements in the parent cell line that does not express PolGdn, to rule out off-target effects of doxycycline treatment.
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| Contributor(s) |
Bao XR, Goldberger O, Mootha VK |
| Citation(s) |
27307216 |
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| Submission date |
Feb 25, 2014 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Xiaoyan Robert Bao |
| E-mail(s) |
bao@molbio.mgh.harvard.edu
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| Organization name |
Massachusetts General Hospital
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| Department |
Molecular Biology
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| Lab |
Vamsi Mootha
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| Street address |
185 Cambridge St. CPZN 6400
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| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02114 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (24)
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| GSM1333927 |
PolGdn cells at 1 d prior to dox treatment |
| GSM1333928 |
PolGdn cells just prior to dox treatment |
| GSM1333929 |
PolGdn cells with 1 d of dox treatment |
| GSM1333930 |
PolGdn cells with 2 d of dox treatment |
| GSM1333931 |
PolGdn cells with 3 d of dox treatment |
| GSM1333932 |
PolGdn cells with 5 d of dox treatment |
| GSM1333933 |
PolGdn cells with 6 d of dox treatment |
| GSM1333934 |
PolGdn cells after 6 d of dox treatment and 1 d of washout |
| GSM1333935 |
PolGdn cells after 6 d of dox treatment and 2 d of washout |
| GSM1333936 |
PolGdn cells after 6 d of dox treatment and 3 d of washout |
| GSM1333937 |
PolGdn cells after 6 d of dox treatment and 4 d of washout |
| GSM1333938 |
PolGdn cells after 6 d of dox treatment and 6 d of washout |
| GSM1333939 |
PolGdn cells after 6 d of dox treatment and 8 d of washout |
| GSM1333940 |
PolGdn cells after 6 d of dox treatment and 10 d of washout |
| GSM1333941 |
PolGdn cells after 6 d of dox treatment and 12 d of washout |
| GSM1333942 |
PolGdn cells after 6 d of dox treatment and 15 d of washout |
| GSM1333943 |
PolGdn cells after 6 d of dox treatment and 17 d of washout |
| GSM1333944 |
PolGdn cells after 6 d of dox treatment and 19 d of washout |
| GSM1333945 |
T-Rex293 cells, untreated control, biological repl 1 |
| GSM1333946 |
T-Rex293 cells, untreated control, biological repl 2 |
| GSM1333947 |
T-Rex293 cells, untreated control, biological repl 3 |
| GSM1333948 |
T-Rex293 cells, 6 d dox treatment, biological repl 1 |
| GSM1333949 |
T-Rex293 cells, 6 d dox treatment, biological repl 2 |
| GSM1333950 |
T-Rex293 cells, 6 d dox treatment, biological repl 3 |
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| Relations |
| BioProject |
PRJNA239305 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE55311_RAW.tar |
142.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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