Chad Weldy, MD, PhD
@chadweldy.bsky.social
Cardiologist and physician-scientist @Stanford | Instructor of Medicine | working to accelerate precision medicine through epigenetics and RNA editing
https://profiles.stanford.edu/chad-weldy
https://profiles.stanford.edu/chad-weldy
Super excited we made the cover of @natcardiovascres.nature.com! Work represents ADAR1 RNA editing within the vascular wall
October 15, 2025 at 1:38 PM
Super excited we made the cover of @natcardiovascres.nature.com! Work represents ADAR1 RNA editing within the vascular wall
There's a lot here and a lot more in the paper. But I get excited thinking about the potential. From rare to complex disease to novel mechanisms with real potential for a precision guided approach to therapy. A lot to do! @stanfordmedicine.bsky.social @stanforddeptmed.bsky.social
September 16, 2025 at 12:48 PM
There's a lot here and a lot more in the paper. But I get excited thinking about the potential. From rare to complex disease to novel mechanisms with real potential for a precision guided approach to therapy. A lot to do! @stanfordmedicine.bsky.social @stanforddeptmed.bsky.social
To then connect this back to humans, entirely grateful for collaborators @clintomics.bsky.social & Sander van der Laan where we investigated ISG activation and SMC modulation and plaque phenotype in the Athero-Express cohort, showing distinct relationships between ISG induction and calcification
September 16, 2025 at 12:48 PM
To then connect this back to humans, entirely grateful for collaborators @clintomics.bsky.social & Sander van der Laan where we investigated ISG activation and SMC modulation and plaque phenotype in the Athero-Express cohort, showing distinct relationships between ISG induction and calcification
Importantly, we define the cellular trajectory of MDA5 activation leading to vascular calcification and disease progression, an effect that can be entirely inhibited with simply haploinsufficiency of MDA5.
September 16, 2025 at 12:48 PM
Importantly, we define the cellular trajectory of MDA5 activation leading to vascular calcification and disease progression, an effect that can be entirely inhibited with simply haploinsufficiency of MDA5.
This MDA5 activation leads to increased plaque size due to increased SMC migration into the plaque with markedly increased vascular calcification.
September 16, 2025 at 12:48 PM
This MDA5 activation leads to increased plaque size due to increased SMC migration into the plaque with markedly increased vascular calcification.
But importantly, we show that with SMC ADAR1 haploinsufficiency, atherosclerosis studies reveal that MDA5 activation occurs in a cell type and context specific mechanism. MDA5 activation drives a distinct SMC cell state change.
September 16, 2025 at 12:48 PM
But importantly, we show that with SMC ADAR1 haploinsufficiency, atherosclerosis studies reveal that MDA5 activation occurs in a cell type and context specific mechanism. MDA5 activation drives a distinct SMC cell state change.
In atherosclerosis - we show that SMCs appear to be enriched for these immunogenic RNA, and that as SMC undergo phenotypic modulation in both human and mouse there is significant activation of ISG genes, potentially suggestive of MDA5 activation
September 16, 2025 at 12:48 PM
In atherosclerosis - we show that SMCs appear to be enriched for these immunogenic RNA, and that as SMC undergo phenotypic modulation in both human and mouse there is significant activation of ISG genes, potentially suggestive of MDA5 activation
With homozygous deletion of ADAR1 in SMC, there is a loss of vascular integrity. Further single cell RNA sequencing reveals distinct ISG activation and cellular infiltration with critical receptor ligand interaction
September 16, 2025 at 12:48 PM
With homozygous deletion of ADAR1 in SMC, there is a loss of vascular integrity. Further single cell RNA sequencing reveals distinct ISG activation and cellular infiltration with critical receptor ligand interaction
Our work here gets at this mechanism.
We reveal a fundamental observation, that vascular SMC have a unique requirement for ADAR1 editing to prevent MDA5 activation.
SMC deletion of ADAR1 leads to severe phenotype within days and is entirely blocked with deletion of MDA5
We reveal a fundamental observation, that vascular SMC have a unique requirement for ADAR1 editing to prevent MDA5 activation.
SMC deletion of ADAR1 leads to severe phenotype within days and is entirely blocked with deletion of MDA5
September 16, 2025 at 12:48 PM
Our work here gets at this mechanism.
We reveal a fundamental observation, that vascular SMC have a unique requirement for ADAR1 editing to prevent MDA5 activation.
SMC deletion of ADAR1 leads to severe phenotype within days and is entirely blocked with deletion of MDA5
We reveal a fundamental observation, that vascular SMC have a unique requirement for ADAR1 editing to prevent MDA5 activation.
SMC deletion of ADAR1 leads to severe phenotype within days and is entirely blocked with deletion of MDA5
The big finding in 2022 by my colleagues Qin Li (now @upenn.edu and Billy Li @stanforduniversity.bsky.social)
was that beyond rare disease, common variants appear to regulate RNA editing (edQTLs), and these edQTLs predict numerous common inflammatory disorders, including CAD! t.co/t1i47lPlGG
was that beyond rare disease, common variants appear to regulate RNA editing (edQTLs), and these edQTLs predict numerous common inflammatory disorders, including CAD! t.co/t1i47lPlGG
September 16, 2025 at 12:48 PM
The big finding in 2022 by my colleagues Qin Li (now @upenn.edu and Billy Li @stanforduniversity.bsky.social)
was that beyond rare disease, common variants appear to regulate RNA editing (edQTLs), and these edQTLs predict numerous common inflammatory disorders, including CAD! t.co/t1i47lPlGG
was that beyond rare disease, common variants appear to regulate RNA editing (edQTLs), and these edQTLs predict numerous common inflammatory disorders, including CAD! t.co/t1i47lPlGG
Amazingly, mice that are deficient in ADAR1 are embryonic lethal, but dual knock out of ADAR1 and MDA5 essentially rescues the phenotype. In this case, the role of ADAR1 seems to be nearly entirely based on preventing MDA5 activation, less so the actual edit of the transcript
September 16, 2025 at 12:48 PM
Amazingly, mice that are deficient in ADAR1 are embryonic lethal, but dual knock out of ADAR1 and MDA5 essentially rescues the phenotype. In this case, the role of ADAR1 seems to be nearly entirely based on preventing MDA5 activation, less so the actual edit of the transcript
In rare disease, loss of ADAR1 causes a severe interferonopathy due to the build up of dsRNA and activation of the dsRNA receptor MDA5 (gene symbol IFIH1). Similarly, gain of function variants in MDA5 (IFIH1) cause the same disorders, including severe vascular calcification
September 16, 2025 at 12:48 PM
In rare disease, loss of ADAR1 causes a severe interferonopathy due to the build up of dsRNA and activation of the dsRNA receptor MDA5 (gene symbol IFIH1). Similarly, gain of function variants in MDA5 (IFIH1) cause the same disorders, including severe vascular calcification
RNA has the peculiar pattern of having long repetitive elements on either end, where these strands fold over on each other to make double strand RNA structures -> turns out this looks a lot like a dsRNA virus!
So why doesn't this dsRNA induce an antiviral response? ADAR1!
So why doesn't this dsRNA induce an antiviral response? ADAR1!
September 16, 2025 at 12:48 PM
RNA has the peculiar pattern of having long repetitive elements on either end, where these strands fold over on each other to make double strand RNA structures -> turns out this looks a lot like a dsRNA virus!
So why doesn't this dsRNA induce an antiviral response? ADAR1!
So why doesn't this dsRNA induce an antiviral response? ADAR1!
When ADAR editing occurs in the coding region of a transcript, it serves as an A -> G edit and can change protein function.
Even in coral and octopus in response to temperature changes of the ocean, whoa!
Although amazingly, the majority of editing sites are non-coding (hmm)
Even in coral and octopus in response to temperature changes of the ocean, whoa!
Although amazingly, the majority of editing sites are non-coding (hmm)
September 16, 2025 at 12:48 PM
When ADAR editing occurs in the coding region of a transcript, it serves as an A -> G edit and can change protein function.
Even in coral and octopus in response to temperature changes of the ocean, whoa!
Although amazingly, the majority of editing sites are non-coding (hmm)
Even in coral and octopus in response to temperature changes of the ocean, whoa!
Although amazingly, the majority of editing sites are non-coding (hmm)
What is RNA editing and how does this relate to coronary artery disease??
There's a lot here but it's fascinating.
A to I editing is an under appreciated area of biology, where ADAR enzymes deaminate adenosine to inosine. Thousands of RNA molecules are edited all the time!
There's a lot here but it's fascinating.
A to I editing is an under appreciated area of biology, where ADAR enzymes deaminate adenosine to inosine. Thousands of RNA molecules are edited all the time!
September 16, 2025 at 12:48 PM
What is RNA editing and how does this relate to coronary artery disease??
There's a lot here but it's fascinating.
A to I editing is an under appreciated area of biology, where ADAR enzymes deaminate adenosine to inosine. Thousands of RNA molecules are edited all the time!
There's a lot here but it's fascinating.
A to I editing is an under appreciated area of biology, where ADAR enzymes deaminate adenosine to inosine. Thousands of RNA molecules are edited all the time!
Through ChromBPNet analysis, by identifying the variants that affect chromatin accessibility in a vascular site specific manner, we identified that many of these variants land in key developmental TF motifs such as MEF2A, HAND2, as well as other regulatory TFs important in disease risk such as SMAD3
September 10, 2025 at 3:54 PM
Through ChromBPNet analysis, by identifying the variants that affect chromatin accessibility in a vascular site specific manner, we identified that many of these variants land in key developmental TF motifs such as MEF2A, HAND2, as well as other regulatory TFs important in disease risk such as SMAD3
Not only can we reveal and predict variant effect on chromatin accessibility, but we define that effect varies by vascular site even within cell type
September 10, 2025 at 3:54 PM
Not only can we reveal and predict variant effect on chromatin accessibility, but we define that effect varies by vascular site even within cell type
But how does this relate to human disease?? Through an awesome collaboration with the @anshulkundaje.bsky.social lab, we trained ChromBPNet models with scATACseq datasets for each cell type and vascular site, and predict human variant effect on a cell type/site basis @soumyakundu.bsky.social
September 10, 2025 at 3:54 PM
But how does this relate to human disease?? Through an awesome collaboration with the @anshulkundaje.bsky.social lab, we trained ChromBPNet models with scATACseq datasets for each cell type and vascular site, and predict human variant effect on a cell type/site basis @soumyakundu.bsky.social
Gene regulatory network analysis through integrated RNA and ATAC datasets across cell types and vascular sites reveal cell type and vascular site specific GRNs, this highlighted ascending fibroblast specific MEOX1
September 10, 2025 at 3:54 PM
Gene regulatory network analysis through integrated RNA and ATAC datasets across cell types and vascular sites reveal cell type and vascular site specific GRNs, this highlighted ascending fibroblast specific MEOX1
Vascular site specific epigenomic patterns are distinct for SMCs, fibroblasts, as well as endothelial cells, but importantly not macrophage cells. While developmental TFs a enriched there are thousands of distinct enhancer elements across vascular sites
September 10, 2025 at 3:54 PM
Vascular site specific epigenomic patterns are distinct for SMCs, fibroblasts, as well as endothelial cells, but importantly not macrophage cells. While developmental TFs a enriched there are thousands of distinct enhancer elements across vascular sites
Many enhancers correspond to developmental origin and highlight specific developmental transcription factors such as HAND2, GATA4, and HOX family members, suggestive of an epigenetic 'memory' of developmental origin
September 10, 2025 at 3:54 PM
Many enhancers correspond to developmental origin and highlight specific developmental transcription factors such as HAND2, GATA4, and HOX family members, suggestive of an epigenetic 'memory' of developmental origin
In our work, by performing single cell RNA and ATAC sequencing across different vascular sites in mice, we reveal that the epigenomic landscape is distinct to not only cell type, but vascular site, defining vascular site specific enhancers
September 10, 2025 at 3:54 PM
In our work, by performing single cell RNA and ATAC sequencing across different vascular sites in mice, we reveal that the epigenomic landscape is distinct to not only cell type, but vascular site, defining vascular site specific enhancers
A critical element of complex genetics is that the majority of GWAS SNPs that influence disease regulate non-coding enhancer elements in the genome — where variants can influence disease risk through regulating cell type specific enhancers, but what about for the vasculature??
September 10, 2025 at 3:54 PM
A critical element of complex genetics is that the majority of GWAS SNPs that influence disease regulate non-coding enhancer elements in the genome — where variants can influence disease risk through regulating cell type specific enhancers, but what about for the vasculature??
However we know that the genetic drivers of complex vascular traits vary based on vascular site, a beautiful example is the exceptional work by @jamespirruccello.com in 2022 showing the different genetic variants that impact ascending versus descending aortic dimension
September 10, 2025 at 3:54 PM
However we know that the genetic drivers of complex vascular traits vary based on vascular site, a beautiful example is the exceptional work by @jamespirruccello.com in 2022 showing the different genetic variants that impact ascending versus descending aortic dimension
Beautiful work in developmental biology going back decades has revealed that vascular diversity has a developmental basis, and that these vascular territories have distinct biology
September 10, 2025 at 3:54 PM
Beautiful work in developmental biology going back decades has revealed that vascular diversity has a developmental basis, and that these vascular territories have distinct biology