From efba813d1df54ec6102337db200216d99bbaa29f Mon Sep 17 00:00:00 2001 From: Lizzy Wilk Date: Fri, 1 May 2026 14:11:07 -0500 Subject: [PATCH 1/5] update readme content with overview, dependencies, scripts, data, etc --- README.Rmd | 88 +++++++++++++++++++++++++++++++++++++++++------------- 1 file changed, 67 insertions(+), 21 deletions(-) diff --git a/README.Rmd b/README.Rmd index 4ad2f4a..f4422d5 100644 --- a/README.Rmd +++ b/README.Rmd @@ -9,28 +9,74 @@ date: "`r Sys.Date()`" knitr::opts_chunk$set(echo = TRUE) ``` -**EDIT THIS DOCUMENT AND KNIT, DO NOT EDIT README.MD DIRECTLY** - -# README Template -**[Replace this header with your project name]** - -## Purpose - -**[Replace this section with the purpose of your research project.]** -This is an R Markdown document created for the Lasseigne Lab R Project Template. The project and README template are designed to create standardized R projects for research ongoing in the [Lasseigne Lab at the University of Alabama at Birmingham](https://www.lasseigne.org/) - - -## Installation/Dependencies OR Scripts - -**[if project will be a package]** - this section should be titled "Installation" -Include a code chunk on how to install your package - -**[if project will not be a package]** - this section should be titled "Dependencies" or "Scripts" -Include a code chunk (if relevant) on what your project depends on. Include a "script tree" on how to reproduce your results with descriptions for all scripts +# SETBP1-HD: Intersection of Regulatory Analysis and Signature Reversion Uncovers Therapeutic Drugs and Targets +## Purpose +This repository contains the code and analysis pipeline for identifying repurposable drugs for SETBP1 Haploinsufficiency Disorder (SETBP1-HD). By deriving a consensus transcriptomic signature from in vitro and in vivo models and integrating it with SETBP1 regulatory targets, we prioritize FDA-approved therapeutics (such as celecoxib and buspirone) capable of reversing disease-associated molecular disruptions. + +## Dependencies +The pipeline utilizes a combination of Conda environments and Docker containers to ensure reproducibility. Below are the environments/images required and the scripts that run within them: +Conda Environment (nfcore-env.yml) +04_human_preprocess.sh +04_mouse_preprocess.sh +Docker: ncbi/sra-tools:3.2.1 +02_fetch_data.sh +Docker: lizzyr/lw_models:0.1.1 +05_data_cleaning.R +06_dataset_eda.R +07_combined_eda.R +Docker: lizzyr/lw_dea:0.3.1 +08_find_degs.R +09_analyze_degs.R +10_consensus_signature.R +permutation_analysis/02_job_permutation.sh +permutation_analysis/03_job_permutation.sh +permutation_analysis/04_job_prioritize.sh +Docker: lizzyr/sigsearch:1.0.0 +11_signature_reversion.R +12_drugtarget_degs.R +Docker: projectassistant/sitemap-scraper:latest +13_drug_safety.py + +## Data +The analyses utilize publicly available RNA-seq datasets mapping to SETBP1 deficiency models: +[GSE180185](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE180185) - Cardo et al.: Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder +GSE262710 - Shaw et al.: Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling +PRJNA898600 (Lin−c-Kit+ cells) - Tanaka et al.: SETBP1 is dispensable for normal and malignant hematopoiesis +PRJNA974068 (Lin−c-Kit+ Sca-1+ cells) - Tanaka et al.: SETBP1 is dispensable for normal and malignant hematopoiesis + +## Scripts +The src/ directory contains the complete pipeline for data fetching, preprocessing, exploratory data analysis (EDA), differential expression analysis (DEA), and drug prioritization. +src/ +├── 01_ref_genome.sh # Downloads and builds reference genome indices. +├── 02_fetch_data.sh # Retrieves raw RNA-seq data from public repositories. +├── 03_fastq_samplesheet_job.sh # Generates sample sheets mapping the downloaded FASTQ files. +├── 04_human_preprocess.sh # Preprocesses raw human reads (QC, alignment, quantification). +├── 04_mouse_preprocess.sh # Preprocesses raw mouse reads (QC, alignment, quantification). +├── 05_data_cleaning.R # Cleans and formats raw count matrices for downstream analysis. +├── 05_job_cleaning.sh +├── 06_dataset_eda.R # Performs Exploratory Data Analysis (EDA) on individual datasets. +├── 06_job_eda.sh +├── 07_combined_eda.R # Evaluates cross-study batch effects and combined data structure. +├── 07_job_combined_eda.sh +├── 08_find_degs.R # Conducts differential expression analysis (DEA) to find significant gene changes. +├── 08_job_dea.sh +├── 09_analyze_degs.R # Analyzes and visualizes the DEGs (e.g., volcano plots, functional enrichment). +├── 09_job_analyze_degs.sh +├── 10_consensus_signature.R # Derives the robust consensus transcriptomic signature across SETBP1-HD models. +├── 10_job_consensus_sig.sh +├── 11_signature_reversion.R # Queries the LINCS database to find drugs that reverse the consensus signature. +├── 11_job_sigsearch.sh +├── 12_drugtarget_degs.R # Intersects drug candidate targets with prioritized SETBP1 regulatory targets. +├── 12_job_drugtarget_degs.sh +├── 13_drug_safety.py # Scrapes and evaluates pediatric/pregnancy safety profiles for top drug candidates. +├── 13_job_drug_safety.sh +├── figures/ # Scripts for generating final publication figures. +├── functions.R # Custom reusable R functions used throughout the pipeline. +└── permutation_analysis/ # Scripts for spatiotemporal permutation testing of SETBP1 targets. ## Authors -List co-authors if known here. +Elizabeth J. Wilk, Sasha Taluri, Tabea M. Soelter, and Brittany N. Lasseigne** ## Lasseigne Lab @@ -40,11 +86,11 @@ List co-authors if known here. ## Funding -List project funding sources. +We are grateful to our funders for this work: the SETBP1 Society (2024 Microgrant) and the UAB Pilot Center for Precision Animal Modeling (C-PAM) (U54-OD030167) ## Acknowledgements -List project acknowledgements. +We thank the Lasseigne Lab members for their thoughtful input and discussion. Additionally, we thank the SETBP1 community of researchers, clinicians, patients, and caregivers for their dedication and hard work to improve the care of those affected by SETBP1 variation. ## License From bcc9d42debe80ac07dbe45ac155a142a2ede0762 Mon Sep 17 00:00:00 2001 From: Lizzy Wilk <69320986+lizzyjoan@users.noreply.github.com> Date: Fri, 1 May 2026 14:41:35 -0500 Subject: [PATCH 2/5] Revise README for SETBP1-HD project overview Updated README with project details, dependencies, and acknowledgments. --- README.md | 120 +++++++++++++++++++++++++++++++++++------------------- 1 file changed, 78 insertions(+), 42 deletions(-) diff --git a/README.md b/README.md index 0a84858..29bfb8c 100644 --- a/README.md +++ b/README.md @@ -1,47 +1,83 @@ -README -================ -2023-02-27 - -**EDIT THIS DOCUMENT, NOT README.md** - -# README Template - -**SETBP1-HD** - +# SETBP1-HD: Intersection of Regulatory Analysis and Signature Reversion Uncovers Therapeutic Drugs and Targets ## Purpose - -**\[Replace this section with the purpose of your research project.\]** -This is an R Markdown document created for the Lasseigne Lab R Project -Template. The project and README template are designed to create -standardized R projects for research ongoing in the [Lasseigne Lab at -the University of Alabama at Birmingham](https://www.lasseigne.org/) - -## Installation/Dependencies OR Scripts - -**\[if project will be a package\]** - this section should be titled -“Installation” Include a code chunk on how to install your package - -**\[if project will not be a package\]** - this section should be titled -“Dependencies” or “Scripts” Include a code chunk (if relevant) on what -your project depends on. Include a “script tree” on how to reproduce -your results with descriptions for all scripts +This repository contains the code and analysis pipeline for identifying repurposable drugs for SETBP1 Haploinsufficiency Disorder (SETBP1-HD). By deriving a consensus transcriptomic signature from in vitro and in vivo models and integrating it with SETBP1 regulatory targets, we prioritize FDA-approved therapeutics (such as celecoxib and buspirone) capable of reversing disease-associated molecular disruptions. + +## Dependencies +The pipeline utilizes a combination of Conda environments and Docker containers to ensure reproducibility. Below are the environments/images required and the scripts that run within them: + +- **Conda Environment (bin/conda/nfcore-env.yml)** + - 04_human_preprocess.sh + - 04_mouse_preprocess.sh +- **Docker: ncbi/sra-tools:3.2.1** + - 02_fetch_data.sh +- **Docker: lizzyr/lw_models:0.1.1** + - 05_data_cleaning.R + - 06_dataset_eda.R + - 07_combined_eda.R +- **Docker: lizzyr/lw_dea:0.3.1** + - 08_find_degs.R + - 09_analyze_degs.R + - 10_consensus_signature.R + - permutation_analysis/02_job_permutation.sh + - permutation_analysis/03_job_permutation.sh + - permutation_analysis/04_job_prioritize.sh +- **Docker: lizzyr/sigsearch:1.0.0** + - 11_signature_reversion.R + - 12_drugtarget_degs.R +- **Docker: projectassistant/sitemap-scraper:latest** + - 13_drug_safety.py ## Data -GSE262710 -- Cardo et al.: [Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling](https://pmc.ncbi.nlm.nih.gov/articles/PMC11443744/) - -GSE180185 -- Shaw et al.: [Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder](https://pmc.ncbi.nlm.nih.gov/articles/PMC9940404/) - -PRJNA898600 (Lin−c-Kit+ cells) -- Tanaka et al.: [SETBP1 is dispensable for normal and malignant hematopoiesis](https://www.nature.com/articles/s41375-023-01970-5) - -PRJNA974068 (Lin−c-Kit+ Sca-1+ cells) -- Tanaka et al.: [SETBP1 is dispensable for normal and malignant hematopoiesis](https://www.nature.com/articles/s41375-023-01970-5) - -## Authors +Cardo et al.: [Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling](https://pmc.ncbi.nlm.nih.gov/articles/PMC11443744/) +- GSE262710 + +Shaw et al.: [Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder](https://pmc.ncbi.nlm.nih.gov/articles/PMC9940404/) +- GSE180185 + +Tanaka et al.: [SETBP1 is dispensable for normal and malignant hematopoiesis](https://www.nature.com/articles/s41375-023-01970-5) +- PRJNA898600 (Lin−c-Kit+ cells) +- PRJNA974068 (Lin−c-Kit+ Sca-1+ cells) + +Wong et al.: [SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder](https://www.nature.com/articles/s41467-025-64074-x) +- GSE301238 (fibroblasts) +- GSE301239 (induced neurons) + +## Scripts +The src/ directory contains the complete pipeline for data fetching, preprocessing, exploratory data analysis (EDA), differential expression analysis (DEA), and drug prioritization. +``` +src/ +├── 01_ref_genome.sh # Downloads and builds reference genome indices. +├── 02_fetch_data.sh # Retrieves raw RNA-seq data from public repositories. +├── 03_fastq_samplesheet_job.sh # Generates sample sheets mapping the downloaded FASTQ files. +├── 04_human_preprocess.sh # Preprocesses raw human reads (QC, alignment, quantification). +├── 04_mouse_preprocess.sh # Preprocesses raw mouse reads (QC, alignment, quantification). +├── 05_data_cleaning.R # Cleans and formats raw count matrices for downstream analysis. +├── 05_job_cleaning.sh +├── 06_dataset_eda.R # Performs Exploratory Data Analysis (EDA) on individual datasets. +├── 06_job_eda.sh +├── 07_combined_eda.R # Evaluates cross-study batch effects and combined data structure. +├── 07_job_combined_eda.sh +├── 08_find_degs.R # Conducts differential expression analysis (DEA) to find significant gene changes. +├── 08_job_dea.sh +├── 09_analyze_degs.R # Analyzes and visualizes the DEGs (e.g., volcano plots, functional enrichment). +├── 09_job_analyze_degs.sh +├── 10_consensus_signature.R # Derives the robust consensus transcriptomic signature across SETBP1-HD models. +├── 10_job_consensus_sig.sh +├── 11_signature_reversion.R # Queries the LINCS database to find drugs that reverse the consensus signature. +├── 11_job_sigsearch.sh +├── 12_drugtarget_degs.R # Intersects drug candidate targets with prioritized SETBP1 regulatory targets. +├── 12_job_drugtarget_degs.sh +├── 13_drug_safety.py # Scrapes and evaluates pediatric/pregnancy safety profiles for top drug candidates. +├── 13_job_drug_safety.sh +├── figures/ # Scripts for generating final publication figures. +├── functions.R # Custom reusable R functions used throughout the pipeline. +└── permutation_analysis/ # Scripts for spatiotemporal permutation testing of SETBP1 targets. +``` + +## Authors + +Elizabeth J. Wilk, Sasha Taluri, Tabea M. Soelter, and Brittany N. Lasseigne -List co-authors if known here. ## Lasseigne Lab @@ -53,11 +89,11 @@ List co-authors if known here. ## Funding -List project funding sources. +We are grateful to our funders for this work: the [SETBP1 Society](https://www.setbp1.org/) (2024 Microgrant) and the [UAB Pilot Center for Precision Animal Modeling (C-PAM)](https://sites.uab.edu/cpam/) (U54-OD030167) ## Acknowledgements -List project acknowledgements. +We thank the Lasseigne Lab members for their thoughtful input and discussion. We also extend our deep gratitude to the SETBP1 Society and the broader community of researchers, clinicians, patients, and caregivers. Your dedication, open sharing of data, and collaborative discussions have been instrumental in advancing this research and improving the care of those affected by SETBP1 variation. ## License From d9ce16e62f0d51acf2f1b50bae2a791450514251 Mon Sep 17 00:00:00 2001 From: Lizzy Wilk <69320986+lizzyjoan@users.noreply.github.com> Date: Fri, 1 May 2026 15:45:55 -0500 Subject: [PATCH 3/5] Update README with formatting and additional details Updated README.md for clarity and added references. --- README.md | 35 ++++++++++++++++++++--------------- 1 file changed, 20 insertions(+), 15 deletions(-) diff --git a/README.md b/README.md index 29bfb8c..520886d 100644 --- a/README.md +++ b/README.md @@ -1,9 +1,9 @@ # SETBP1-HD: Intersection of Regulatory Analysis and Signature Reversion Uncovers Therapeutic Drugs and Targets ## Purpose -This repository contains the code and analysis pipeline for identifying repurposable drugs for SETBP1 Haploinsufficiency Disorder (SETBP1-HD). By deriving a consensus transcriptomic signature from in vitro and in vivo models and integrating it with SETBP1 regulatory targets, we prioritize FDA-approved therapeutics (such as celecoxib and buspirone) capable of reversing disease-associated molecular disruptions. +This repository contains the code and analysis pipeline for identifying repurposable drugs for * *SETBP1* * Haploinsufficiency Disorder (* *SETBP1* *-HD). By deriving a consensus transcriptomic signature from * *in-vitro* * models and integrating it with * *SETBP1* * regulatory targets, we prioritize FDA-approved therapeutics (such as celecoxib and buspirone) capable of reversing disease-associated molecular disruptions. ## Dependencies -The pipeline utilizes a combination of Conda environments and Docker containers to ensure reproducibility. Below are the environments/images required and the scripts that run within them: +This codebase was built using the [CAPTURE](https://github.com/lasseignelab/capture) framework (cap version 1.0) and uses a combination of Conda environments and Docker containers to ensure reproducibility. Below are the environments/images required and the scripts that run within them: - **Conda Environment (bin/conda/nfcore-env.yml)** - 04_human_preprocess.sh @@ -28,19 +28,17 @@ The pipeline utilizes a combination of Conda environments and Docker containers - 13_drug_safety.py ## Data -Cardo et al.: [Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling](https://pmc.ncbi.nlm.nih.gov/articles/PMC11443744/) -- GSE262710 +- **Signature reversion drug repurposing analyses:** + - GSE262710: **Cardo et al.** [Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling](https://pmc.ncbi.nlm.nih.gov/articles/PMC11443744/) + - GSE180185: **Shaw et al.** [Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder](https://pmc.ncbi.nlm.nih.gov/articles/PMC9940404/) + - PRJNA898600 (Lin−c-Kit+ cells) & PRJNA974068 (Lin−c-Kit+ Sca-1+ cells): **Tanaka et al.** [SETBP1 is dispensable for normal and malignant hematopoiesis](https://www.nature.com/articles/s41375-023-01970-5) + - GSE301238 (fibroblasts) & GSE301239 (induced neurons): **Wong et al.** [SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder](https://www.nature.com/articles/s41467-025-64074-x) -Shaw et al.: [Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder](https://pmc.ncbi.nlm.nih.gov/articles/PMC9940404/) -- GSE180185 +- **Regulatory target prioritization & permutation testing:** + - [GTEx](https://gtexportal.org/home/downloads/adult-gtex/overview) 2025-08-22 v11 RNASeQCv2.4.3 TPM and metadata files [v11 Sample and Subject Attributes DS] + - [dGTEx](https://gtexportal.org/home/downloads/developmental-gtex) 2025-07-21 v1 RNASeQCv2.4.3 TPM and metadata files [v1 2026-01-30 Sample and Subject Attributes]) + - [BrainSpan](https://www.brainspan.org/static/download.html) api v2, developmental transcriptome zip file with expression matrix, row metadata [genes], column metadata [samples]) -Tanaka et al.: [SETBP1 is dispensable for normal and malignant hematopoiesis](https://www.nature.com/articles/s41375-023-01970-5) -- PRJNA898600 (Lin−c-Kit+ cells) -- PRJNA974068 (Lin−c-Kit+ Sca-1+ cells) - -Wong et al.: [SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder](https://www.nature.com/articles/s41467-025-64074-x) -- GSE301238 (fibroblasts) -- GSE301239 (induced neurons) ## Scripts The src/ directory contains the complete pipeline for data fetching, preprocessing, exploratory data analysis (EDA), differential expression analysis (DEA), and drug prioritization. @@ -71,7 +69,14 @@ src/ ├── 13_job_drug_safety.sh ├── figures/ # Scripts for generating final publication figures. ├── functions.R # Custom reusable R functions used throughout the pipeline. -└── permutation_analysis/ # Scripts for spatiotemporal permutation testing of SETBP1 targets. +└── permutation_analysis/ + ├── 01_fetch_temporal_exp.sh # Fetches BrainSpan and GTEx temporal gene expression data. + ├── 02_job_permutation.sh + ├── 02_spatiotemporal_perm.R # Performs permutation testing to identify critical developmental windows for SETBP1 targets. + ├── 03_job_permutation.sh + ├── 03_postnatal_development.R # Analyzes SETBP1 target expression shifts during the prenatal-to-postnatal transition. + ├── 04_job_prioritize.sh + └── 04_prioritize_targets.R # Prioritizes targets based on spatiotemporal co-expression, core pathways, and known druggability. ``` ## Authors @@ -93,7 +98,7 @@ We are grateful to our funders for this work: the [SETBP1 Society](https://www.s ## Acknowledgements -We thank the Lasseigne Lab members for their thoughtful input and discussion. We also extend our deep gratitude to the SETBP1 Society and the broader community of researchers, clinicians, patients, and caregivers. Your dedication, open sharing of data, and collaborative discussions have been instrumental in advancing this research and improving the care of those affected by SETBP1 variation. +We thank the Lasseigne Lab members for their thoughtful input and discussion. We also extend our deep gratitude to the * *SETBP1* * Society and the broader community of researchers, clinicians, patients, and caregivers. Your dedication, open sharing of data, and collaborative discussions have been instrumental in advancing this research and improving the care of those affected by * *SETBP1* * variation. ## License From 48bd46e760cc9386db85074800e82bd51e50b84d Mon Sep 17 00:00:00 2001 From: Lizzy Wilk Date: Fri, 1 May 2026 15:47:48 -0500 Subject: [PATCH 4/5] rm old readme template --- README.Rmd | 97 ------------------------------------------------------ 1 file changed, 97 deletions(-) delete mode 100644 README.Rmd diff --git a/README.Rmd b/README.Rmd deleted file mode 100644 index f4422d5..0000000 --- a/README.Rmd +++ /dev/null @@ -1,97 +0,0 @@ ---- -title: "README" -author: -output: github_document -date: "`r Sys.Date()`" ---- - -```{r setup, include=FALSE} -knitr::opts_chunk$set(echo = TRUE) -``` - -# SETBP1-HD: Intersection of Regulatory Analysis and Signature Reversion Uncovers Therapeutic Drugs and Targets -## Purpose -This repository contains the code and analysis pipeline for identifying repurposable drugs for SETBP1 Haploinsufficiency Disorder (SETBP1-HD). By deriving a consensus transcriptomic signature from in vitro and in vivo models and integrating it with SETBP1 regulatory targets, we prioritize FDA-approved therapeutics (such as celecoxib and buspirone) capable of reversing disease-associated molecular disruptions. - -## Dependencies -The pipeline utilizes a combination of Conda environments and Docker containers to ensure reproducibility. Below are the environments/images required and the scripts that run within them: -Conda Environment (nfcore-env.yml) -04_human_preprocess.sh -04_mouse_preprocess.sh -Docker: ncbi/sra-tools:3.2.1 -02_fetch_data.sh -Docker: lizzyr/lw_models:0.1.1 -05_data_cleaning.R -06_dataset_eda.R -07_combined_eda.R -Docker: lizzyr/lw_dea:0.3.1 -08_find_degs.R -09_analyze_degs.R -10_consensus_signature.R -permutation_analysis/02_job_permutation.sh -permutation_analysis/03_job_permutation.sh -permutation_analysis/04_job_prioritize.sh -Docker: lizzyr/sigsearch:1.0.0 -11_signature_reversion.R -12_drugtarget_degs.R -Docker: projectassistant/sitemap-scraper:latest -13_drug_safety.py - -## Data -The analyses utilize publicly available RNA-seq datasets mapping to SETBP1 deficiency models: -[GSE180185](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE180185) - Cardo et al.: Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder -GSE262710 - Shaw et al.: Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling -PRJNA898600 (Lin−c-Kit+ cells) - Tanaka et al.: SETBP1 is dispensable for normal and malignant hematopoiesis -PRJNA974068 (Lin−c-Kit+ Sca-1+ cells) - Tanaka et al.: SETBP1 is dispensable for normal and malignant hematopoiesis - -## Scripts -The src/ directory contains the complete pipeline for data fetching, preprocessing, exploratory data analysis (EDA), differential expression analysis (DEA), and drug prioritization. -src/ -├── 01_ref_genome.sh # Downloads and builds reference genome indices. -├── 02_fetch_data.sh # Retrieves raw RNA-seq data from public repositories. -├── 03_fastq_samplesheet_job.sh # Generates sample sheets mapping the downloaded FASTQ files. -├── 04_human_preprocess.sh # Preprocesses raw human reads (QC, alignment, quantification). -├── 04_mouse_preprocess.sh # Preprocesses raw mouse reads (QC, alignment, quantification). -├── 05_data_cleaning.R # Cleans and formats raw count matrices for downstream analysis. -├── 05_job_cleaning.sh -├── 06_dataset_eda.R # Performs Exploratory Data Analysis (EDA) on individual datasets. -├── 06_job_eda.sh -├── 07_combined_eda.R # Evaluates cross-study batch effects and combined data structure. -├── 07_job_combined_eda.sh -├── 08_find_degs.R # Conducts differential expression analysis (DEA) to find significant gene changes. -├── 08_job_dea.sh -├── 09_analyze_degs.R # Analyzes and visualizes the DEGs (e.g., volcano plots, functional enrichment). -├── 09_job_analyze_degs.sh -├── 10_consensus_signature.R # Derives the robust consensus transcriptomic signature across SETBP1-HD models. -├── 10_job_consensus_sig.sh -├── 11_signature_reversion.R # Queries the LINCS database to find drugs that reverse the consensus signature. -├── 11_job_sigsearch.sh -├── 12_drugtarget_degs.R # Intersects drug candidate targets with prioritized SETBP1 regulatory targets. -├── 12_job_drugtarget_degs.sh -├── 13_drug_safety.py # Scrapes and evaluates pediatric/pregnancy safety profiles for top drug candidates. -├── 13_job_drug_safety.sh -├── figures/ # Scripts for generating final publication figures. -├── functions.R # Custom reusable R functions used throughout the pipeline. -└── permutation_analysis/ # Scripts for spatiotemporal permutation testing of SETBP1 targets. - -## Authors - -Elizabeth J. Wilk, Sasha Taluri, Tabea M. Soelter, and Brittany N. Lasseigne** - -## Lasseigne Lab - -[What is Happening in the Lasseigne Lab?](https://www.lasseigne.org/) - - - -## Funding - -We are grateful to our funders for this work: the SETBP1 Society (2024 Microgrant) and the UAB Pilot Center for Precision Animal Modeling (C-PAM) (U54-OD030167) - -## Acknowledgements - -We thank the Lasseigne Lab members for their thoughtful input and discussion. Additionally, we thank the SETBP1 community of researchers, clinicians, patients, and caregivers for their dedication and hard work to improve the care of those affected by SETBP1 variation. - -## License - -This repository is licensed under the MIT License, see LICENSE documentation within this repository for more details. From 0934ee364cdabb4b2000ab6f83ffb95a3d38cf0a Mon Sep 17 00:00:00 2001 From: Lizzy Wilk <69320986+lizzyjoan@users.noreply.github.com> Date: Tue, 5 May 2026 09:53:55 -0500 Subject: [PATCH 5/5] Fixed formatting and references in README --- README.md | 16 ++++++++-------- 1 file changed, 8 insertions(+), 8 deletions(-) diff --git a/README.md b/README.md index 520886d..995e879 100644 --- a/README.md +++ b/README.md @@ -1,6 +1,6 @@ -# SETBP1-HD: Intersection of Regulatory Analysis and Signature Reversion Uncovers Therapeutic Drugs and Targets +# *SETBP1*-HD: Intersection of Regulatory Analysis and Signature Reversion Uncovers Therapeutic Drugs and Targets ## Purpose -This repository contains the code and analysis pipeline for identifying repurposable drugs for * *SETBP1* * Haploinsufficiency Disorder (* *SETBP1* *-HD). By deriving a consensus transcriptomic signature from * *in-vitro* * models and integrating it with * *SETBP1* * regulatory targets, we prioritize FDA-approved therapeutics (such as celecoxib and buspirone) capable of reversing disease-associated molecular disruptions. +This repository contains the code and analysis pipeline for identifying repurposable drugs for *SETBP1* Haploinsufficiency Disorder (*SETBP1*-HD). By deriving a consensus transcriptomic signature from *in-vitro* models and integrating it with *SETBP1* regulatory targets, we prioritize FDA-approved therapeutics (such as celecoxib and buspirone) capable of reversing disease-associated molecular disruptions. ## Dependencies This codebase was built using the [CAPTURE](https://github.com/lasseignelab/capture) framework (cap version 1.0) and uses a combination of Conda environments and Docker containers to ensure reproducibility. Below are the environments/images required and the scripts that run within them: @@ -18,9 +18,9 @@ This codebase was built using the [CAPTURE](https://github.com/lasseignelab/capt - 08_find_degs.R - 09_analyze_degs.R - 10_consensus_signature.R - - permutation_analysis/02_job_permutation.sh - - permutation_analysis/03_job_permutation.sh - - permutation_analysis/04_job_prioritize.sh + - permutation_analysis/02_spatiotemporal_perm.R + - permutation_analysis/03_postnatal_development.R + - permutation_analysis/04_prioritize_targets.R - **Docker: lizzyr/sigsearch:1.0.0** - 11_signature_reversion.R - 12_drugtarget_degs.R @@ -29,8 +29,8 @@ This codebase was built using the [CAPTURE](https://github.com/lasseignelab/capt ## Data - **Signature reversion drug repurposing analyses:** - - GSE262710: **Cardo et al.** [Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling](https://pmc.ncbi.nlm.nih.gov/articles/PMC11443744/) - - GSE180185: **Shaw et al.** [Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder](https://pmc.ncbi.nlm.nih.gov/articles/PMC9940404/) + - GSE180185: **Cardo et al.** [Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder](https://pmc.ncbi.nlm.nih.gov/articles/PMC9940404/) + - GSE262710: **Shaw et al.** [Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling](https://pmc.ncbi.nlm.nih.gov/articles/PMC11443744/) - PRJNA898600 (Lin−c-Kit+ cells) & PRJNA974068 (Lin−c-Kit+ Sca-1+ cells): **Tanaka et al.** [SETBP1 is dispensable for normal and malignant hematopoiesis](https://www.nature.com/articles/s41375-023-01970-5) - GSE301238 (fibroblasts) & GSE301239 (induced neurons): **Wong et al.** [SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder](https://www.nature.com/articles/s41467-025-64074-x) @@ -98,7 +98,7 @@ We are grateful to our funders for this work: the [SETBP1 Society](https://www.s ## Acknowledgements -We thank the Lasseigne Lab members for their thoughtful input and discussion. We also extend our deep gratitude to the * *SETBP1* * Society and the broader community of researchers, clinicians, patients, and caregivers. Your dedication, open sharing of data, and collaborative discussions have been instrumental in advancing this research and improving the care of those affected by * *SETBP1* * variation. +We thank the Lasseigne Lab members for their thoughtful input and discussion. We also extend our deep gratitude to the *SETBP1* Society and the broader community of researchers, clinicians, patients, and caregivers. Your dedication, open sharing of data, and collaborative discussions have been instrumental in advancing this research and improving the care of those affected by *SETBP1* variation. ## License