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Massively Parallel Characterization of Transcriptional Regulatory Elements in Three Diverse Human Cell Types by Vikram Agarwal; Fumitaka Inoue; Max Schubach; Beth K. Martin; Pyaree Mohan Dash; Zicong Zhang; Ajuni Sohota; William Stafford Noble; Galip Gürkan Yardimci; Martin Kircher; Jay Shendure; Nadav Ahituv is a scholarly article available to read on EtoBox.

What is Massively Parallel Characterization of Transcriptional Regulatory Elements in Three Diverse Human Cell Types about?

The human genome contains millions of candidate __cis__-regulatory elements (CREs) with cell-type-specific activities that shape both health and myriad disease states. However, we lack a functional understanding of the sequence features that control the activity and cell-type-specific features of these CREs. Here, we used lentivirus-based massively parallel reporter assays (lentiMPRAs) to test the regulatory activity of over 680,000 sequences, representing a nearly comprehensive set of all annotated CREs among three cell types (HepG2, K562, and WTC11), finding 41.7% to be functional. By testing sequences in both orientations, we find promoters to have significant strand orientation effects. We also observe that their 200 nucleotide cores function as non-cell-type-specific ‘on switches’ providing similar expression levels to their associated gene. In contrast, enhancers have weaker orientation effects, but increased tissue-specific characteristics. Utilizing our lentiMPRA data, we develop sequence-based models to predict CRE function with high accuracy and delineate regulatory motifs. Testing an additional lentiMPRA library encompassing 60,000 CREs in all three cell types, we furthe

Author

Vikram Agarwal; Fumitaka Inoue; Max Schubach; Beth K. Martin; Pyaree Mohan Dash; Zicong Zhang; Ajuni Sohota; William Stafford Noble; Galip Gürkan Yardimci; Martin Kircher; Jay Shendure; Nadav Ahituv

Publisher

Cold Spring Harbor Laboratory

Published

2023

Language

EN