Largest catalog yet of how human cells read DNA shows how chemical marks alter genetic instructions
Every cell in the body contains essentially the same DNA, yet a brain cell behaves differently from a muscle cell or an immune cell. The difference lies largely in how each cell reads its genetic instructions.
Human cells express identical DNA yet function differently depending on the cell type—brain, muscle, immune system, etc. Proteins called transcription factors bind to specific DNA sequences, controlling when and where genes are active, directing processes from development to immunity. When this regulation fails, disease can arise.
Scientists at the University of Toronto have compiled a vast catalog of how human cells read DNA, illuminating how chemical marks alter genetic instructions. Using five experimental platforms and computational analyses, they identified DNA-binding motifs for 177 transcription factors previously poorly understood, adding roughly 130 new motifs to the known vocabulary of human gene regulation.
This extensive catalogue, dubbed a "Codebook," represents the most comprehensive collection of transcription factor binding preferences to date. Bart Deplancke's lab at EPFL was instrumental in creating this resource. However, DNA also carries chemical modifications like methylation that influence gene regulation without altering the sequence.
In a separate paper, Deplancke's team developed meSMiLE-seq, a microfluidic method comparing transcription factor binding to both methylated and unmethylated DNA simultaneously. Applying this technique to 114 transcription factors, they obtained DNA-binding models for 48, revealing that 14 factors show greater affinity for methylated DNA or recognize alternative methylation-dependent motifs, while 13 exhibit reduced affinity.
These findings indicate that many transcription factors effectively "read" an additional layer of information on top of the DNA sequence itself. The combined studies expand the catalog of DNA sequences recognized by human transcription factors and demonstrate how DNA methylation modifies these interactions. Together, the Codebook and meSMiLE-seq study provide a richer understanding of how cells interpret genetic instructions, potentially enhancing the interpretation of genetic variants linked to disease, explaining why identical DNA sequences behave differently in various cell types, and deepening our understanding of development, aging, and diseases like cancer.
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