Dr. Ofir Hakim

A major question in our research is how cell-selective transcription program, which is the basis for cell type-specific functions, is progressively modulated during differentiation, faithfully transmitted through cell division, and attenuated to respond to external stimuli.

To address this question, we are studying three linked layers of transcription regulation:

1. Transcription factor action.

2. Chromatin accessibility.

3. Three-dimensional (3D) genome organization.

Two of the critical determinants of gene expression patterns are the cooperative activity of multiple transcription factors, and selective accessibility of regulatory DNA elements. These two regulatory layers are tightly linked because transcription factors preferentially associate with accessible chromatin, and recruit chromatin remodeling enzymes that regulate this accessibility.

Intriguingly, global mapping of regulatory DNA by ChIP and DHS experiments revealed that genes and regulatory elements mainly reside at great distance from the regulated genes. Hence, the study of the genome as linear is highly over-simplified. The use of chromosome conformation capture (3C) technology to detect long-range chromosomal interactions, has uncovered that regulatory elements loop over great genomic distances to their target loci, in complex association configurations, to exert their regulatory role.

Above the scale of local genomic contacts, spatial congregation of genomic regions from different chromosomes, and from distant chromosomal loci, together with protein factors, give rise to functionally compartmentalized nuclear space. Non-random genome folding within the nuclear space is emerging as key contributor for regulating nuclear processes. The lab is focused on understanding the molecular basis of genome architecture and deciphering the regulatory role of nuclear topology, primarily in the context of gene expression.

For studying how the transcription program is regulated, we use ChIP-seq to uncover target loci of specific transcription factors, and DHS-seq for identifying DNA regulatory elements of known and novel transcription factors. Furthermore, we apply 'C' technologies (3C, 4C, Hi-C) to unravel the folding patterns of the genome, to catalogue genes with their distant regulatory loci, and to characterize their nuclear spatial environment. Important aspect of our work is the use of high-resolution, high-throughput microscopy, to study the organization of genomic loci and nuclear functions. This unique merge of genomics and imaging is a powerful approach to understand the population data at the single-cell level.

To address the biological questions, we combine studies in mammalian and plant model systems. We study the immediate transcriptional response of human T cells and Arabidopsis root cells to external signals, and we study the regulation of transcription programs during T-cell differentiation.