Exploring the Role of Enhancer-Mediated Transcriptional Regulation in Precision Biology

Abstract

The emergence of precision biology has been driven by the development of advanced technologies and techniques in high-resolution biological research systems. Enhancer-mediated transcriptional regulation, a complex network of gene expression and regulation in eukaryotes, has attracted significant attention as a promising avenue for investigating the underlying mechanisms of biological processes and diseases. To address biological problems with precision, large amounts of data, functional information, and research on the mechanisms of action of biological molecules is required to address biological problems with precision. Enhancers, including typical enhancers and super enhancers, play a crucial role in gene expression and regulation within this network. The identification and targeting of disease-associated enhancers hold the potential to advance precision medicine. In this review, we present the concepts, progress, importance, and challenges in precision biology, transcription regulation, and enhancers. Furthermore, we propose a model of transcriptional regulation for multi-enhancers and provide examples of their mechanisms in mammalian cells, thereby enhancing our understanding of how enhancers achieve precise regulation of gene expression in life processes. Precision biology holds promise in providing new tools and platforms for discovering insights into gene expression and disease occurrence, ultimately benefiting individuals and society as a whole.

Keywords: enhancer-mediated; precision biology; three-dimensional (3D) genomics; transcriptional regulation.

Figure 1

List of technologies that promote the development of precision biology. The multidimensional resolution of precision biology (inner circle), the advancement of precision biology through various enabling milestones through different translational axes, such as high-throughput research methods and big data analysis and integration (outer frame).

Figure 2

Transcription initiation complex binding enhancer and promoter. The enhancer (yellow sequence) binds to mediator complex of transcription initiation complex. It can interact with the promoter (orange sequence) bound to Pol II. The same promoter may bind different enhancers in different cells. The promoter interacts with the second enhancer in cell A and the same promoter interacts with the first enhancer in cell B.

Figure 3

Comparison of typical enhancer (TE), super enhancer (SE) and multi-enhancer (ME) interoperability patterns. (1) TE usually positively drives target gene expression and more transcripts are generated. E denotes a single enhancer. (2) SE is usually a cluster of enhancers consisting of neighboring enhancers. SE has a stronger effect on gene transcription enhancement than TE. It can help to produce more transcripts. E1 to En denote different enhancers. (3) In ME modulation, enhancers may be distributed at different positions of the gene and may be far from the gene, such as E1 or be adjacent to the gene, such as E2. Each enhancer can enhance gene expression, but the resulting transcriptions may be different. Different transcriptions are shown in different colours.

Figure 4

Three enhancers of the Sox2 gene show different kinds of E-P associations. Different interaction patterns differentiate ESC into different cells. Active enhancers enh.1, enh.2, and enh.3 are shown in green, blue, and brown, respectively. Inactive enhancers are shown in gray with “×” mark. Black arrow indicates the direction of transcription initiation.

Figure 5

CNS0, CNS1, CNS2, and CNS3 have different effects on Foxp3. (1) CNS1 interacts with the Foxp3 promoter to induce iTreg cell generation in intestine-associated lymphoid tissues. (2) Foxp3 expression in the progeny of dividing Treg cells is dependent on CNS2, (3) CNS3 increases the frequency of Treg cells generated in the thymus and periphery and maintains cellular homeostasis. (4) Compared with wild type, deletion of CNS0 and CNS3 partially disrupted thymic Treg cell production, resulting in morphological alterations in mice. (5) Deletion of both CNS0 and CNS3 completely prevented the production of thymic Treg cells, resulting in further imbalance in tissue morphology.