Enhancers are DNA regulatory elements that control gene transcription. During development, dynamic control of enhancer activity drives the changes in gene expression underlying cell fate specification. We seek to understand the mechanisms controlling where and when enhancers are used. In particular, we focus on the mechanisms controlling physical access to enhancer DNA in chromatin. Enhancer activity is determined by transcription factor binding. In vivo, DNA is packaged into nucleosomes, the repeating unit of chromatin. Generally-speaking, nucleosomes act as a barrier to transcription factor binding. By contrast, nucleosome-depleted DNA (also known as “open chromatin”) is generally permissive to transcription factor binding. Hence, regulation of chromatin accessibility is a fundamental step in control of enhancer activity.
What are the factors that open chromatin?
What are the factors that close chromatin?
What co-regulators are involved?
How are spatial and temporal regulatory cues integrated?
We employ a combination of approaches to answer these questions, including a range of genomics assays (ATAC-seq/FAIRE-seq, CUT&RUN/ChIP-seq, RNA-seq), Drosophila genetics, CRISPR, microscopy, and biochemistry.
Recent Relevant Publications:
Elife. 2020; eLife.58305. PMID: 32490812
Nystrom* SL, Niederhuber* MJ, McKay DJ. Expression of E93 provides an instructive cue to control dynamic enhancer activity and chromatin accessibility during development. Development.2020; 147(6). PMID: 32094114
Ma Y, McKay DJ, Buttitta L. Changes in chromatin accessibility ensure robust cell cycle exit in terminally differentiated cells. PLoS Biology. 2019 Sep 3;17(9):e3000378. PMID: 31479438.
Uyehara CM, McKay DJ. Direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila. Proc Natl Acad Sci USA. 2019 Apr 24. PMID: 31019084.
Lai YT, Deem KD, Borràs-Castells F, Sambrani N, Rudolf H, Suryamohan K, El-Sherif E, Halfon MS, McKay DJ, Tomoyasu Y. Enhancer identification and activity evaluation in the red flour beetle, Tribolium castaneum. Development. 2018; 145(7). PMID: 29540499.
Uyehara CM, Nystrom SL, Niederhuber MJ, Leatham-Jensen M, Ma Y, Buttitta LA, McKay DJ. Hormone-dependent control of developmental timing through regulation of chromatin accessibility. Genes & Development. 2017 May 1;31(9):862-875. PMCID: PMC5458754.
Pearson JC*, McKay DJ*#, Lieb JD, and Crews ST#. Chromatin profiling of Drosophila CNS subpopulations identifies active transcriptional enhancers. Development. 2016 Oct 15;143(20):3723-3732. PMCID: PMC5087646.
McKay DJ#, Lieb JD#. A common set of DNA regulatory elements shapes Drosophila appendages. Developmental Cell. 2013; 27: 306-318. PMID: 24229644.