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Stress-induced glucocorticoid signaling impairs enteric neurotrophin BDNF-TrkB pathway and drives gastrointestinal dysmotility.

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The authors' code

R Markdown · 206 lines · 7.1 KB · no license

  1. ---
  2. title: "isoform switch"
  3. author: "Jared Slosberg"
  4. date: "6/22/2023"
  5. output: html_document
  6. ---
  8. Script needs to be run with R = 4.2.
  9. Use /opt/R/4.2.3/bin/R with libraries @ "/home/jared/R/x86_64-pc-linux-gnu-library/4.2".
  10. Singularity container with isoformAnalysis.yml
  11. Saturn = 1.7.3
  12. IsoformSwitchAnalyzer = 2.1.2
  14. ```{r setup, include=FALSE}
  15. .libPaths("/home/jared/R/x86_64-pc-linux-gnu-library/4.2")
  16. knitr::opts_chunk$set(echo = TRUE)
  17. ```
  19. ```{r, message = F}
  20. #library(tidyverse)
  21. library(here)
  22. library(IsoformSwitchAnalyzeR)
  23. library(dplyr)
  24. ```
  26. From the isoform quantification IsoformSwitchAnalyzeR performs five high-level tasks:
  28. - Statistical identification of isoform switches.
  30. - Integration of a wide range of (predicted) annotations for the isoforms involved in the identified switches (e.g. protein domains).
  32. - Identification of which isoforms have a predicited functional consequnce (e.g. loss/gain of protein domain).
  34. - Visualization of predicted consequences of the isoform switches for individual genes
  36. - Analysis of genome wide patterns in both switch consequences and alternative splicing.
  39. ```{r}
  40. metadata <- read.csv(here("metadata_merged.csv")) %>% filter(sample_name != "17mo-M-1")
  41. design <- metadata %>% transmute(sampleID = sample_name, condition = age) %>% mutate(
  42. condition = paste0("age_",condition)
  43. )
  45. #needs names
  46. #path_to_quant <- here("kallisto_out_merged", metadata$sample_name, "abundance.tsv")
  48. kallistoQuant <- importIsoformExpression(
  49. parentDir = here("kallisto_out_merged"),
  50. addIsofomIdAsColumn = TRUE
  51. )
  53. aSwitchList <- importRdata(
  54. isoformCountMatrix = kallistoQuant$counts,
  55. isoformRepExpression = kallistoQuant$abundance,
  56. designMatrix = design,
  57. isoformExonAnnoation = here("isoform_level_analysis/gencode.vM27.annotation.gtf"),
  58. showProgress = T
  59. )
  60. ```
  61. Differential testing and downstream isoform fraction comparisons
  62. ```{r}
  64. #lowered geneExpressionCutoff to include BDNF
  65. aSwitchList_filt <- preFilter(aSwitchList, geneExpressionCutoff = 0.28, isoformExpressionCutoff = 0, removeSingleIsoformGenes = T)
  67. SwitchRes <- isoformSwitchTestDEXSeq(aSwitchList_filt, reduceToSwitchingGenes = F)
  69. saveRDS(SwitchRes, here("isoform_level_analysis/isoformSwitchAnalyzer/DEXSeq/DEXSeq_res.rds"))
  70. ```
  72. Prepare and plot isoform fractions
  73. ```{r}
  74. condition_list <- list("17mo_vs_P30" = c("cond1" = "age_17mo", "cond2" = "age_P30"),
  75. "17mo_vs_6mo" = c("cond1" = "age_17mo", "cond2" = "age_6mo"),
  76. "6mo_vs_P30" = c("cond1" = "age_6mo", "cond2" = "age_P30"))
  78. pl_list <- purrr::map(names(condition_list), function(cond){
  79. print(cond)
  80. print(condition_list[[cond]][1])
  82. pdf(paste0(here("isoform_level_analysis/isoformSwitchAnalyzer/DEXSeq/plots/BDNF_isoforms_"), cond, ".pdf"), onefile = F)
  85. switchPlot(
  86. SwitchRes,
  87. gene='Bdnf',
  88. IFcutoff = 0,
  89. condition1 = condition_list[[cond]][1],
  90. condition2 = condition_list[[cond]][2],
  91. rescaleTranscripts = F# making text sightly larger for vignette
  92. )
  94. dev.off()
  98. })
  100. ages <- c("age_17mo","age_6mo")
  101. iso_fraction_df <- purrr::map_df(ages, function(age){
  102. iso_fractions <- SwitchRes$isoformFeatures %>% filter(gene_id == "Bdnf", condition_1 == age) %>% dplyr::select(gene_id, isoform_id, IF1) %>% unique %>% mutate(age = age, IF = IF1) %>% dplyr::select(gene_id, age, isoform_id, IF)
  104. })
  106. iso_fractions <- SwitchRes$isoformFeatures %>% filter(gene_id == "Bdnf", condition_2 == "age_P30") %>% dplyr::select(gene_id, isoform_id, IF2) %>% unique %>% mutate(age = "age_P30", IF = IF2) %>% dplyr::select(gene_id, age, isoform_id, IF)
  108. iso_fraction_df <- rbind(iso_fraction_df, iso_fractions) %>%
  109. mutate(pct = paste0(round(IF * 100, 1), " %")) %>%
  110. mutate(pct = str_replace_all(pct, "0 %", "")) %>%
  111. mutate(age_clean = str_replace_all(age, "age_", "")) %>%
  112. mutate(age_clean = factor(str_replace_all(age_clean, "P30", "1mo"), levels = c("1mo","6mo","17mo")))
  114. #change ensmust names to common e.g. BDNF-201
  115. bdnf_meta <- read.csv(here("isoform_level_analysis/data/bdnf_isoform_description.csv"))
  116. iso_fraction_df <- iso_fraction_df %>%
  117. tidyr::separate(., col= "isoform_id", into = c("transcript_id","version"), sep ="\\.") %>% right_join(., bdnf_meta) %>%
  118. mutate(isoform_id = paste0(isoform, " (", exon_id, ")"))
  120. pl <- ggplot(iso_fraction_df, aes(x = age_clean, y = IF, fill = isoform_id)) +
  121. geom_col(position = "fill", color = "black") +
  122. ggtitle("Isoform Expression of Bdnf") +
  123. ylab("Isoform fraction") +
  124. xlab("Age") +
  125. geom_text(aes(label = pct), position = "stack", vjust = 1.1, size= 3)+
  126. scale_fill_brewer(palette = "RdYlBu") +
  127. theme_minimal() +
  128. theme(panel.grid.major.x = element_blank())
  129. pl
  131. pdf(here("isoform_level_analysis/isoformSwitchAnalyzer/DEXSeq/plots/BDNF_isoforms_all_ages.pdf"))
  132. pl
  133. dev.off()
  135. write.csv(iso_fraction_df, here("isoform_level_analysis/isoformSwitchAnalyzer/DEXSeq/plots/BDNF_isoform_fractions.csv"))
  136. ```
  139. Check trkB expression
  140. ```{r}
  141. iso_counts <- aSwitchList$isoformCountMatrix
  142. gene_df <- aSwitchList$isoformFeatures[,c("isoform_id","gene_id")]
  143. iso_counts <- full_join(iso_counts, gene_df) %>% relocate(isoform_id, gene_id)
  144. ```
  146. Plot TrkB expression
  147. ```{r}
  148. pl_list <- purrr::map(names(condition_list), function(cond){
  149. print(cond)
  150. print(condition_list[[cond]][1])
  152. pdf(paste0(here("isoform_level_analysis/isoformSwitchAnalyzer/DEXSeq/plots/TrkB_isoforms_"), cond, ".pdf"), onefile = F)
  155. switchPlot(
  156. SwitchRes,
  157. gene='Ntrk2',
  158. IFcutoff = 0,
  159. condition1 = condition_list[[cond]][1],
  160. condition2 = condition_list[[cond]][2],
  161. rescaleTranscripts = T
  162. )
  164. dev.off()
  168. })
  170. #todo: easier to grab IF values by condition from SwitchRes$isoformRepIF
  171. ages <- c("age_17mo","age_6mo")
  172. iso_fraction_df <- purrr::map_df(ages, function(age){
  173. iso_fractions <- SwitchRes$isoformFeatures %>% filter(gene_id == "Ntrk2", condition_1 == age) %>% dplyr::select(gene_id, isoform_id, IF1) %>% unique %>% mutate(age = age, IF = IF1) %>% dplyr::select(gene_id, age, isoform_id, IF)
  175. })
  177. iso_fractions <- SwitchRes$isoformFeatures %>% filter(gene_id == "Ntrk2", condition_2 == "age_P30") %>% dplyr::select(gene_id, isoform_id, IF2) %>% unique %>% mutate(age = "age_P30", IF = IF2) %>% dplyr::select(gene_id, age, isoform_id, IF)
  179. iso_fraction_df <- rbind(iso_fraction_df, iso_fractions) %>%
  180. mutate(pct = paste0(round(IF * 100, 1), " %")) %>%
  181. mutate(pct = str_replace_all(pct, "0 %", "")) %>%
  182. mutate(pct = ifelse(IF > 0.03, pct, "")) %>%
  183. mutate(age_clean = str_replace_all(age, "age_", "")) %>%
  184. mutate(age_clean = factor(str_replace_all(age_clean, "P30", "1mo"), levels = c("1mo","6mo","17mo")))
  186. pl <- ggplot(iso_fraction_df, aes(x = age_clean, y = IF, fill = isoform_id)) +
  187. geom_col(position = "fill", color = "black") +
  188. ggtitle("Isoform Expression of Ntrk2") +
  189. ylab("Isoform fraction") +
  190. xlab("Age") +
  191. geom_text(aes(label = pct), position = "stack", vjust = 1.1, size= 3)+
  192. scale_fill_brewer(palette = "RdYlBu") +
  193. theme_minimal() +
  194. theme(panel.grid.major.x = element_blank())
  195. pl
  197. pdf(here("isoform_level_analysis/isoformSwitchAnalyzer/DEXSeq/plots/TrkB_isoforms_all_ages.pdf"))
  198. pl
  199. dev.off()
  202. write.csv(iso_fraction_df, here("isoform_level_analysis/isoformSwitchAnalyzer/DEXSeq/plots/TrkB_isoform_fractions.csv"))
  203. ```

BDNF_expression.Rmd at commit 23eadb7, no license · at the source

Overview

Authors: Jared Slosberg1, Srinivas N Puttapaka2, Philippa Seika2, Su Min Hong2, Alpana Singh3, Gamze Sonmez2,4, Ainsleigh Scott2,5, Subhash Kulkarni2,6,7
ORCID iDs: Jared Slosberg, Alpana Singh, Gamze Sonmez, Subhash Kulkarni
  1. Department of Genetic Medicine, Johns Hopkins University – School of Medicine, Baltimore, Maryland, USA
  2. Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  3. Cleveland Clinic, Cleveland, Ohio, USA
  4. Department of Medical Biochemistry, Hacettepe University Faculty of Medicine, Ankara, Turkey
  5. Graduate Program in Medical Sciences, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA
  6. Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA
  7. Graduate Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA
Institutions: Johns Hopkins University (United States); Johns Hopkins Medicine (United States); Beth Israel Deaconess Medical Center (United States); Harvard University (United States); Cleveland Clinic (United States); Hacettepe University (Türkiye); Boston University (United States)
Journal: The Journal of biological chemistry, volume 302, issue 7, article 113095
Dates: received 15 October 2025; published online 27 April 2026; in print July 2026
Type: Research article · Language: English
License: CC BY-NC-ND
Identifiers: DOI 10.1016/j.jbc.2026.113095 · PMID 42055341 · PMCID PMC13273678 · OpenAlex W7156127373
Open access: gold, a free copy (OpenAlex)
Status: code verified
Categories: mouse (organism), cellular / molecular (subfield)
Methods: Smoothing, state filtering, decompositions, Evoked potentials, Statistics
Keywords: BDNF, enteric nervous system, restraint stress, TrkB, glucocorticoid signalin
MeSH: Brain-Derived Neurotrophic Factor*, Enteric Nervous System*, Gastrointestinal Motility*, Glucocorticoids*, Receptor, trkB*, Signal Transduction*, Animals, Female, Male, Mice, Mice, Inbred C57BL (* major topic)
Topic: Gastrointestinal motility and disorders (Gastroenterology, Medicine), according to OpenAlex
Funding: National Institute on Aging (R 01AG066768, R21AG072107); NIA NIH HHS (R01 AG066768, R21 AG072107); Harvard Digestive Diseases Center; Harvard Catalyst; National Cancer Institute; National Institute of General Medical Sciences (T32GM148383); Augusta University Medical College of Georgia; Beth Israel Deaconess Medical Center; Harvard University; NIGMS NIH HHS (T32 GM148383); NCATS NIH HHS (UM1 TR004408); Burroughs Wellcome Fund; Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (528835020); National Center for Advancing Translational Sciences; Augusta University; German Research Foundation; National Institutes of Health
Citations: cited by 1 paper (Europe PMC); 61 references in the paper

Abstract

The abstract is not reproduced here: the paper's license (CC BY-NC-ND) does not allow it. Read it in the paper, at the publisher or on Europe PMC.

Repository

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jaredslosberg/timecourse_lmmp_bulkrnaseq

License: none: the authors keep all their rights
State: the link answers, verified on 30 September 2026
Evidence: files inventoried
Commit: 23eadb7dde5a1a0ac9be7485e0003165a0dc3d1d, 18 December 2024
Languages: R (26), Shell (4)
Size: 50 files, 30 scripts
Software Heritage: not archived
Found in: “Data availability”
Holds: README, environment (renv.lock), 16 notebooks
Not found: license file, CITATION.cff, tests, continuous integration, documentation
Tools: tidyverse (21 files), DESeq2 (16 files), ComplexHeatmap (9 files), ggpubr (6 files), clusterProfiler (2 files), ggplot2 (2 files), Monocle 3 (2 files), caret (1 file), circlize (1 file), UMAP (1 file)
Availability: 1 check, the latest on 30 September 2026: the link answers
  • 30 September 2026: the link answers
31 files
At the source: github.com/jaredslosberg/timecourse_lmmp_bulkrnaseq/

The paper's code and data availability statement is in the Data section.

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Recorded: type, language, journal, volume, issue, pages, dates, 8 authors, 5 keywords, 11 MeSH terms, 17 funders, 61 references.

Cite

This paper

Slosberg, J., Puttapaka, S. N., Seika, P., Hong, S. M., Singh, A., Sonmez, G., Scott, A., & Kulkarni, S. (2026). Stress-induced glucocorticoid signaling impairs enteric neurotrophin BDNF-TrkB pathway and drives gastrointestinal dysmotility. The Journal of biological chemistry, 302(7), 113095. https://doi.org/10.1016/j.jbc.2026.113095

BibTeX

@article{slosberg2026stress,
author = {Slosberg, Jared and Puttapaka, Srinivas N and Seika, Philippa and Hong, Su Min and Singh, Alpana and Sonmez, Gamze and Scott, Ainsleigh and Kulkarni, Subhash},
title = {{Stress-induced glucocorticoid signaling impairs enteric neurotrophin BDNF-TrkB pathway and drives gastrointestinal dysmotility}},
journal = {The Journal of biological chemistry},
year = {2026},
month = apr,
volume = {302},
number = {7},
pages = {113095},
publisher = {American Society for Biochemistry and Molecular Biology},
issn = {0021-9258},
doi = {10.1016/j.jbc.2026.113095},
url = {https://doi.org/10.1016/j.jbc.2026.113095},
pmid = {42055341},
pmcid = {PMC13273678}
}

RIS

TY - JOUR
AU - Slosberg, Jared
AU - Puttapaka, Srinivas N
AU - Seika, Philippa
AU - Hong, Su Min
AU - Singh, Alpana
AU - Sonmez, Gamze
AU - Scott, Ainsleigh
AU - Kulkarni, Subhash
TI - Stress-induced glucocorticoid signaling impairs enteric neurotrophin BDNF-TrkB pathway and drives gastrointestinal dysmotility
T2 - The Journal of biological chemistry
J2 - J Biol Chem
PY - 2026
DA - 2026/04/27
VL - 302
IS - 7
SP - 113095
SN - 0021-9258
PB - American Society for Biochemistry and Molecular Biology
DO - 10.1016/j.jbc.2026.113095
UR - https://doi.org/10.1016/j.jbc.2026.113095
LA - en
ER -

CSL-JSON

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"title": "Stress-induced glucocorticoid signaling impairs enteric neurotrophin BDNF-TrkB pathway and drives gastrointestinal dysmotility",
"container-title": "The Journal of biological chemistry",
"author": [
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"family": "Slosberg",
"given": "Jared"
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{
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"given": "Ainsleigh"
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"container-title-short": "J Biol Chem",
"volume": "302",
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"DOI": "10.1016/j.jbc.2026.113095",
"PMID": "42055341",
"PMCID": "PMC13273678",
"ISSN": "0021-9258",
"publisher": "American Society for Biochemistry and Molecular Biology",
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"language": "en",
"issued": {
"date-parts": [
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27
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