Transfer learning reveals sequence determinants of the quantitative response to transcription factor dosage

Processed data and code for "Transfer learning reveals sequence determinants of the quantitative response to transcription factor dosage," Naqvi et al 2024.

Directory is organized into 4 subfolders, each tar'ed and gzipped:

data_analysis.tar.gz - Processed data for modulation of TWIST1 levels and calculation of RE responsiveness to TWIST1 dosage

• atac_design.txt - design matrix for ATAC-seq TWIST1 titration samples
• all.sub.150bpclust.greater2.500bp.merge.TWIST1.titr.ATAC.counts.txt - ATAC-seq counts from all samples over all reproducible ATAC-seq peak regions, as defined in Naqvi et al 2023
• atac_deseq_fitmodels_moded50.R - R code for calculating new version of ED50 and response to full depletion from TWIST1 titration data (note, uses drm.R function from 10.5281/zenodo.7689948, install drc() with this version to avoid errors)

baseline_models.tar.gz - Code and data for training baseline models to predict RE responsiveness to SOX9/TWIST1 dosage

• {sox9|twist1}.{0v100|ed50}.{train|valid|test}.txt - Training/testing/validation data (ED50 or full TF depletion effect for SOX9 or TWIST1), split into train/test/validation folds
• HOCOMOCOv11_core_HUMAN_mono_jaspar_format.all.sub.150bpclust.greater2.500bp.merge.minus300bp.p01.maxscore.mat.cpg.gc.basemean.txt.gz - matrix of predictors for all REs. Quantitative encoding of PWM match for all HOCOMOCO motifs + CpG + GC content, plus unperturbed ATAC-seq signal
• train_baseline.R - R code to train baseline (LASSO regression or random forest) models using predictor matrix and the provided training data.
  • Note: training the random forest to predict full TF depletion is computationally intensive because it is across all REs, if doing this run on CPU for ~6 hrs. 

chrombpnet_models.tar.gz - Remainder of code, data, and models for fine-tuning and interpreting ChromBPNet mdoels to predict RE responsiveness to SOX9/TWIST1 dosage

• Fine-tuning code, data, models
  • {all|sox9.direct|twist1.bound.down}.{train|valid|test}.{ed50|0v100.log2fc}.txt - Training/testing/validation data (ED50 or full TF depletion effect for SOX9 or TWIST1), split into train/test/validation folds
  • pretrained.unperturbed.chrombpnet.h5 - Pretrained model of unperturbed ATAC-seq signal in CNCCs, obtained by running ChromBPNet (https://github.com/kundajelab/chrombpnet) on DMSO-treated SOX9/TWIST1-tagged ATAC-seq data
  • finetune_chrombpnet.py - code for fine-tuning the pretrained model for any of the relevant prediction tasks (ED50/ effect of full TF depletion for SOX9/TWIST1)
  • best.model.chrombpnet.{0v100|ed50}.{sox9|twist1}.h5 - output of finetune_chrombpnet.py, best model after 10 training epochs for the indicated task
  • chrombpnet.{0v100|ed50}.{sox9|twist1}.contrib.{h5|bw} - contribution scores for the indicated predictive model, obtained by running chrombpnet contribs_bw on the corresponding model h5 file.
  • chrombpnet.{0v100|ed50}.{sox9|twist1}.contrib.modisco.{h5|bw} - TF-MoDIsCo output from the corresponding contribution score file
• Interpretation code, data, models
  • contrib_h5_to_projshap_npy.py - code to convert contrib .h5 files into .npy files containing projected SHAP scores (required because the CWM matching code takes this format of contribution scores)
  • sox9.direct.10col.bed, twist1.bound.down.10col.uniq.bed - regions over which CWMs will be matched (likely direct targets of each TF)
  • match_cwms.py - Python code to match individual CWM instances. Takes as input: modisco .h5 file, SHAP .npy file, bed file of regions to be matched. Output is a bed file of all CWM matches (not pruned, contains many redundant matches).
  • chrombpnet.ed50.{sox9|twist1}.contrib.perc05.matchperc10.allmatch.bed - output of match_cwms.py 
  • take_max_overlap.py - code to merge output of match_cwms.py into clusters, and then take the maximum (length-normalized) match score in each cluster as the representative CWM match of that cluster. Requires upstream bedtools commands to be piped in, see example usage in file. 
  • chrombpnet.ed50.{sox9|twist1}.contrib.perc05.matchperc10.allmatch.maxoverlap.bed - output of  take_max_overlap.py. These CWM instances are the ones used throughout the paper.

modisco_reports.zip - TF-MoDIsCo reports from running on the fine-tuned ChromBPNet models

• modisco_report_{sox9|twist1}_{0v100|ed50}: folders containing images of discovered CWMs and HTMLs/PDFs of summarized reports from running TF-MoDisCo on the indicated fine-tuned ChromBPNet model

mirny_model.tar.gz - Code and data for analyzing and fitting Mirny model of TF-nucleosome competition to observed RE dosage response curves

• twist1.strong.multi.only.ed50.cutoff.true.hill.txt - ED50 and signed hill coefficients for all TWIST1-dependent REs with only buffering Coordinators (mostly one or two) and no other TFs' binding sites. "ed50_new" is the ED50 calculation used in this paper. 
• twist1.strong.weak{1|2|3}.ed50.cutoff.true.hill.txt - ED50 and signed hill coefficients for all TWIST1-dependent REs with only buffering Coordinators (mostly one or two) and the indicated number of sensitizing (weak) Coordinators and no other TFs' binding sites. "ed50_new" is the ED50 calculation used in this paper. 
• MirnyModelAnalysis.py - Python code for analysis of Mirny model of TF-nucleosome competition. Contains implementations of analytic solutions, as well as code to fit model to observed ED50 and hill coefficients in the provided data files.