Defining RNA polymerase II transcription units across the mammalian genome

Every time a cell reads a gene to make a protein or a regulatory RNA, it must also decide exactly where to stop reading — and that stopping point is far less precise than textbooks suggest. This research tackles a fundamental gap in genomics: we know how cells start transcribing genes, but the rules for where and how they end transcription remain poorly defined, especially for the thousands of long noncoding RNAs (lncRNAs) that pervade mammalian genomes. The team will map termination sites for both protein-coding and lncRNA genes, and dissect the molecular machinery — including several endonucleases and the "torpedo" enzyme XRN2 — that cuts the RNA chain to signal the stop. They will also investigate a newly discovered class of lncRNA promoters that depend on R-loops, three-stranded nucleic acid structures, and examine how histone genes, which lack standard termination signals, manage to stop. This is fundamental science. It does not aim to cure a disease or build a device. But as genome sequencing of normal and diseased human cells accelerates, knowing where genes actually begin and end is essential for interpreting which mutations matter. Without accurate maps of transcription units, researchers cannot tell whether a DNA change disrupts a gene, an enhancer, or a piece of junk. Past work on transcription termination has already revealed mechanisms that underpin RNA-based therapies and cancer diagnostics; this project will sharpen that foundation.