🧚 MethFormer: A Transformer for DNA Methylation

MethFormer is a masked regression transformer model trained to learn local and long-range patterns in DNA methylation (5mC and 5hmC) across genomic regions. Pretrained on binned methylation data, it is designed for downstream fine-tuning on tasks such as predicting MLL binding or chromatin state.

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🚀 Overview

• Inputs: Binned methylation values (5mC, 5hmC) over 1024bp windows (32 bins × 2 channels)
• Pretraining objective: Masked methylation imputation (per-bin regression)
• Architecture: Transformer encoder with linear projection head
• Downstream tasks: MLL binding prediction, chromatin state inference, or enhancer classification

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📁 Project Structure

.
├── config/                       # config
├── data/                         # Binned methylation datasets (HuggingFace format)
├── output/                       # Pretrained models, logs, and checkpoints
├── scripts/                      
│   ├── methformer.py             # Model classes, data collator, 
│   ├── pretrain_methformer.py    # Main training script
│   └── finetune_mll.py           # (optional) downstream fine-tuning
├── requirements.txt
└── README.md

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👩‍💻 Pretraining MethFormer

Step 1: Prepare Dataset

Preprocess 5mC and 5hmC data into 1024bp windows, binned into 32 bins × 2 features. Save using Hugging Face's datasets.DatasetDict format:

DatasetDict({
  train: Dataset({
    features: ['input_values', 'attention_mask', 'labels']
  }),
  validation: Dataset(...)
})

Step 2: Run Pretraining

python scripts/pretrain_methformer.py

Options can be customized inside the script or modified for sweep tuning. This will:

• Train the model using masked regression loss
• Evaluate on a held-out chromosome (e.g., chr8)
• Log metrics to Weights & Biases
• Save the best model checkpoint

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📊 Metrics

• masked_mse: Mean squared error over unmasked positions
• masked_mae: Mean absolute error

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🧪 Fine-tuning on MLL Binding

After pretraining:

1. Replace the regression head with a scalar head for MLL prediction.
2. Use a Trainer to fine-tune on log1p-transformed MLL-N RPKM values mean over 1kb regions.

See scripts/finetune_mll.py for an example.

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🔍 Visualizations & Interpretability

You can run Captum or SHAP for:

• Per-bin attribution of 5mC/5hmC to MLL binding
• Visualizing what MethFormer attends to during fine-tuning

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🛠️ Dependencies

Key packages:

• transformers
• datasets
• wandb
• torch
• anndata
• scikit-learn

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🧠 Acknowledgements

• Built with inspiration from DNABERT, Grover, and vision transformers