Cistrome plasticity and mechanisms of cistrome reprogramming

Abstract

Mammalian genomes contain thousands of cis-regulatory elements for each transcription factor (TF), but TFs only occupy a relatively small subset referred to as cistrome. Recent studies demonstrate that a TF cistrome might differ among different organisms, tissue types and individuals. In a cell, a TF cistrome might differ among different physiological states, pathological stages and between physiological and pathological conditions. It is, therefore, remarkable how highly plastic these binding profiles are, and how massively they can be reprogrammed in rapid response to intra/extracellular variations and during cell identity transitions and evolution. Biologically, cistrome reprogramming events tend to be followed by changes in transcriptional outputs, thus serving as transformative mechanisms to synchronically alter the biology of the cell. In this review, we discuss the molecular basis of cistrome plasticity and attempt to integrate the different mechanisms and biological conditions associated with cistrome reprogramming. Emerging data suggest that, when altered, these reprogramming events might be linked to tumor development and/or progression, which is a radical conceptual change in our mechanistic understanding of cancer and, potentially, other diseases.

Figure 1. TF cistromes are highly plastic binding profiles. Some TFs have been predicted to display dynamic cistromes in rapid response to extracellular signals or circadian clocks way before there was the technology (ChIP-chip/seq) to profile these patterns. Surprisingly, however, when these patterns have been finally profiled, it has been discovered that there is not just a single pattern of induced cistrome, but rather might be a rich repertoire depending on the type of stimuli, intra/extracellular conditions and cell identity, and other factors. Hence, an unstimulated cistrome A may shift between different types of stimulated cistromes, B, C, D, E or F (A). Similarly, a constitutive cistrome or an unstimulated dynamic cistrome may also shift between different profiles (B).

Figure 2.

Known crosstalk between different TF cistromes. (A) TF cistromes often overlap at promoter and enhancer regions, which favor their crosstalk. (B) Some TF cistromes antagonize other TF cistromes, which leads to their mutual exclusion (compare top and bottom). (C) A TF cistrome may so heavily determine another TF cistrome that antagonizes its formation at other genomic sites (top). In the absence of the first cistrome, the second displays a different pattern (bottom).

Figure 3. Overview of biological situations and cellular conditions linked to cistrome plasticity. (A) Variations of extracellular signals. (B) Variations in time of exposure to extracellular signals and, potentially, aging. (C) Variations in cell identity. (D) Variations in physiological state. (E) Variations in pathological state in disease. (F) Viral infection. (G) Evolution. For details, see text.

Figure 4. Overview of molecular mechanisms inducing cistrome reprogramming. (A) Variations in levels of associated TF partners. (B) Genetic mutations or translocations affecting TFs. (C) Genetic variations (SNPs or polymorphism) affecting binding sites. (D) Variations in alternative splicing affecting TFs. (E) Variations in long ncRNAs. For details, see text.