Mapping the regulatory wiring of the genome

Congratulations to the team in the Lander and Guttman labs for three of our major papers (all published in the last few weeks):

(1)  Systematic mapping of functional enhancer-promoter connections with CRISPR interference (Science)

This paper was a phenomenal collaboration with a graduate student in the lab, Charlie Fulco.  We sought to address a fundamental challenge in modern biology: to understand the regulatory wiring that connects noncoding regulatory elements to specific target genes. These connections are typically studied on a one-by-one basis — by knocking out individual sequence elements and determining their effects on gene expression — but there are potentially millions of regulatory elements and we lack a unifying framework to predict their functions.

We developed an approach based on CRISPR interference that can simultaneously assess megabases of sequence in a single experiment — the scale needed to comprehensively define all of the elements that regulate a gene of interest in a given cell type.  Applying this technique revealed complex networks connecting multiple enhancers with multiple target genes. These data allowed us to derive a model that could accurately predict gene-enhancer connections in the MYC locus based on chromatin state alone. This method will be a key tool for interpreting disease-associated human genetic variation and manipulating gene expression for therapeutic purposes.

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(2)  Local regulation of gene expression by lncRNA promoters, transcription, and splicing (Nature)

This paper is the culmination of my PhD thesis with Eric Lander, and has important implications for understanding the variety of different mechanisms that can contribute to the regulatory wiring described above.  Specifically, we found that many sequence signals involved in gene regulation are hiding in unexpected places: many gene promoters act as DNA elements to regulate a neighboring gene, and sequences involved in transcription and RNA processing (e.g., 5′ splice sites) of one gene can also regulate a neighboring gene.

These findings indicate that many genes have dual functions:  they produce an RNA (e.g., a lncRNA or mRNA); and, in doing so, they can regulate the expression of a neighboring gene.  Thus, the expression of a one gene is often directly tied to the expression of its neighbor.  This observation has important implications for the functions of lncRNAs — more (opinionated) commentary to come!

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(3)  Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression (Nature Reviews Molecular Cell Biology)

This review with Mitch Guttman and Noah Ollikainen focuses on the functions and mechanisms of a subset of lncRNAs that function as regulatory RNAs in the nucleus. Such lncRNAs have a unique capability that distinguishes them from protein regulators or DNA regulatory elements: they can spatially amplify regulatory information encoded by DNA. Unlike proteins, lncRNAs can act in close proximity to their site of transcription; and unlike DNA regulatory elements, lncRNAs can amplify DNA-encoded regulatory signals to different extents according to their expression levels. Furthermore, lncRNAs are not necessarily restricted by topological constraints of the chromatin fibre, allowing them to diffuse to or mediate contacts at spatially proximal sites that might even reside on different chromosomes. This properties may explain the molecular functions of lncRNAs like XIST, FIRRE, and others.

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