The eukaryotic genome is highly organized. This is critical for efficient and precise access and regulation of individual genes in the enormous and often highly compact genomes. Therefore, the higher order chromatin structure and the epigenetic organization of the genome can directly impact selective gene activation during animal development and physiological responses. Mutations in DNA and protein components that regulate the epigenome have also been implicated in various human diseases. However, despite intense research efforts, mechanisms that facilitate these epigenetic regulations are still poorly understood.
A focus of my lab is to understand how a unique class of regulatory DNA called chromatin boundary elements (CBE) are involved in organizing genes into functional domains. CBEs, also called insulators, are unique in their ability to block transcription signals from regulatory DNA called enhancers to gene promoters. Experimental evidence suggests that CBE located at different locus in the genome can interact with each other and tether chromatin fibers into “loop domains”. Such loop domains can either disrupt or promote interactions between distant enhancer and promoters, causing changes in gene expression. Recent results from my lab further suggest that interactions between CBE are developmentally regulated to allow the formation of tissue- or stage-specific loops to facilitate gene regulation.
An example CBE we are currently investigating, the SF1, is located in the Drosophila Antennapedia homeotic gene complex (see Figure). Homeotic genes control the developmental identify of animal body segments and are conserved from flies to human. The Sex comb reduced (Scr) gene, for example, is expressed in the labial and first thoracic segment and controls the identity of these segments. The tissue- and developmental stage-specific expression of Scr are controlled by many enhancers, including some that are located far away on the distal side of neighboring gene fushi tarazu (ftz). In addition, the proper maintenance of the Scr pattern also requires the organization of active or repressive chromatin structure. The SF1 boundary, located between Scr and ftz, may organize the local chromatin fiber into tissue and developmental stages-specific chromatin loops, and facilitates independent regulation of the Scr and its neighboring genes (detail see Figure and caption). The knowledge we learned from SF1 study provides important guidance to the understanding of the role of chromatin and genome organization in regulating diverse developmental and disease processes.
Other research interests in the lab include regulation of cell death and growth control, cell and tissue dynamics during Drosophila organogenesis and neural development.
Modulation of chromatin boundary activities by nucleosome-remodeling activities in Drosophila melanogaster. Li M, Belozerov VE, Cai HN. Mol Cell Biol. 2010 Feb;30(4):1067-76. Epub 2009 Dec 7.
Diverse transcription influences can be insulated by the Drosophila SF1 chromatin boundary.
Analysis of chromatin boundary activity in Drosophila cells.
Nuclear location of a chromatin insulator in Drosophila melanogaster.
A novel boundary element may facilitate independent gene regulation in the Antennapedia complex of Drosophila.
The functional analysis of insulator interactions in the Drosophila embryo.
Genomic context modulates insulator activity through promoter competition.
Effects of cis arrangement of chromatin insulators on enhancer-blocking activity.
I M, Ma Z, Liu K, Patel S, Roy S, Lane DC, and Cai HN. Dynamic interactions between the boundary-like elements regulate enhancer access by organizing chromatin loop domains in Drosophila Hox cluster Mol Cell Biol. 2015 34(23): 4018-4029
Branch A, Bobilev A, Negrao NW, Cai H, Shen P. Prevention of palatable diet-induced hyperphagia in rats by central injection of a VEGFR kinase inhibitor. Behav Brain Res. 2015 Feb 1:278:506-13
Ma Z, Li M, Liu JK, Roy s, Patel SK, Lane DC and Cai HN. Chromatin boundary elements organize genome architecture and developmental gene regulation the Drosophila Hox clusters. World Journal of Biological Chemistry 2016 7(3): 223