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![Page 1: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/1.jpg)
Mohamad Ali NajiaSummer Fellow, Bioinformatics and Integrative Genomics Program
Harvard-MIT Division of Health Sciences and Technology
Department of Cancer Biology, Dana-Farber Cancer InstituteHarvard Medical School
Allele-Specific DNA Methylation and Monoallelically Expressed Genes
![Page 2: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/2.jpg)
Monoallelic Expression
Serizawa et al. 2000
Monoallelic Biallelic
X
~10% of all autosomal genes present monoallelic expression
Gimelbrant et al. 2007
Biological Mechanism(s): Unknown Temporal onset? Cell types affected? Regulatory mechanisms?
Biological Importance
MP
DNA Methylation Challenge Previous detection approaches noisy
![Page 3: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/3.jpg)
Mechanistic Insights into Autosomal MAE
Hypothesis: Monoallelically expressed genes present an allele-specific difference in DNA methylation in clonal cell populations
Does allele-specific DNA methylation correspond to allele-specific expression?
XClone 1 M
P
XClone 2 M
P
Clone 3 MP
![Page 4: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/4.jpg)
Multiplex Padlock Probes
Reference Allele
Alternative Allele
AT
C
C
C
C
C
T
T
T
A
GGGG
AA
C
Zhang et al. 2009
Lymphoblast clones
C TBisulfite Conversion
Amplification
Padlock Probes
T
Differential Methylation Score
-1
Alternative Allele Bias Reference Allele Bias
0 +1
𝑠𝑐𝑜𝑟𝑒=(𝐶𝑟−𝐶𝑎)
∑𝐶
![Page 5: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/5.jpg)
Padlock Probe Method Validation
A
B
C
D
E
F
![Page 6: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/6.jpg)
Enriched Allele-Specific MethylationA
B
*
*
**
C
* = p << 0.0001
Annotate SNP Neighborhood
![Page 7: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/7.jpg)
Allelic Bias CategorizationOpposite Bias Same Bias
Clone 1
Clone 2
RA
RA
No Bias
![Page 8: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/8.jpg)
Clone-Specific MAE and Allele-Specific Methylation
* = p << 0.0001
A B
*
*
*
*
All CpGs Upstream CpGs
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Conclusions
• Padlock probe technology can detect allele-specific methylation associated with X chromosome inactivation
• Allele-specific methylation is enriched with allele-specific gene expression on autosomes
• Genes that show clone-specific monoallelic expression are highly enriched with clone and allele specific methylation
![Page 10: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/10.jpg)
Future Work
MAE Gene
MAE Gene
Maternal
Paternal
MAE Gene
MAE Gene
Maternal
Paternal
Clone 1 Clone 2
Gene Expression
Does clone and allele specific DNA methylation correlate with the level of gene expression?
![Page 11: Mohamad Ali Najia Summer Fellow, Bioinformatics and Integrative Genomics Program Harvard-MIT Division of Health Sciences and Technology Department of Cancer.](https://reader037.fdocuments.in/reader037/viewer/2022110320/56649cae5503460f94972035/html5/thumbnails/11.jpg)
Acknowledgements
Gimelbrant Lab:Alexander Gimelbrant, PhD (PI)Virginia Savova, PhDAnwesha Nag, PhDSébastien Vigneau, PhDJason Alvarez
Sponsors/Funding Sources:National Institutes of HealthNational Science Foundationi2b2 National Center for BiocomputingHarvard-MIT Division of Health Sciences and Technology (HST)Massachusetts Institute of TechnologyHarvard Medical SchoolDana-Farber Cancer Institute
Harvard-MIT HST Summer Institute:Susanne Churchill, PhDSonal Jhaveri, PhDBarbara Mawn