Many have seen a world of opportunities open with the release of artificial intelligence-based tools to the public; now, an all-seeing team has combined CRISPR technology with “transposase-accessible chromatin with visualization,” aka ATAC-see, to open a whole epigenome of possibilities by identifying novel chromatin regulators!
The team, headed by the “visionary” Yusuke Miyanari (Kanazawa University), recognized the functional association between chromatin accessibility and transcriptional networks/cell identity but knew that the molecular mechanisms/networks underpinning chromatin accessibility on a genome-wide scale remain somewhat unknown. Therefore, his team combined genome-wide CRISPR screening with ATAC-see to identify those factors modulating chromatin accessibility. ATAC-see uses the Tn5 transposase to insert labeled adapter DNAs into accessible chromatin to globally visualize and quantify chromatin accessibility at single-cell resolution with a high sensitivity/signal-to-noise ratio.
Let’s hear from Ishii and Colleagues on how identifying novel chromatin regulators opens an epigenome of possibilities:
- The search for novel chromatin regulators reveals already described genes such as CREBBP and EP400
- This approach also identifies previously unrecognized chromatin accessibility modulators that belong to diverse biological pathways, such as DNA-templated reactions (including transcription, DNA repair, and DNA replication), RNA processing, N-terminal protein acetylation, and protein translation/degradation
- Novel chromatin regulators include TFDP1, HNRNPU, EIF3D, and THAP11
- ATAC-seq analysis after gene knockout uncovers distinct and specific effects on chromatin accessibility of the identified novel chromatin regulators
- Of note, the transcription factor TFDP1 modulates global chromatin accessibility through the direct transcriptional regulation of canonical histones
- The global elevation of chromatin accessibility after TFDP1 depletion enhances DNA-associated applications that include induced pluripotent stem cell reprogramming
- Importantly, extensive manipulation of chromatin accessibility (as seen for double knockdown for TFDP1/TFDP2 or high-dose treatment with an E2F inhibitor) prompts the misregulation of gene expression through mechanisms such as off-target protein binding or slowing of cell growth
- These findings suggest a need to fine-tune local/global chromatin accessibility to control chromatin plasticity
This far-seeing study has opened our eyes to the multitude of chromatin regulatory factors that function across the epigenome; specifically, the authors allowed us to “ATAC-see” how the TFDP1-mediated transcriptional regulation of canonical histones can impact chromatin accessibility. The team behind this study also underscores the exciting applications of their research: the manipulation of chromatin accessibility to improve cell engineering applications!
To visualize how novel chromatin regulators open an epigenome of possibilities, head over to Nature Genetics, February 2024.