Mechanisms of Enhancer-Promoter Interactions in Higher Eukaryotes

Kyrchanova, Olga; Georgiev, Pavel

doi:10.3390/ijms22020671

Cited by 50 publications

(32 citation statements)

References 194 publications

(189 reference statements)

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“…The system described here has allowed us to reveal novel aspects of the role that the remodeler plays in enhancer-dependent transcription, thus extending our knowledge about molecular mechanisms of enhancer action [74,75]. Moreover, recent data point to a localization of the remodeler on chromatin boundaries and its role in the formation of the global chromatin structure [15,[76][77][78].…”

Section: Discussionmentioning

confidence: 84%

Subunits of the PBAP Chromatin Remodeler Are Capable of Mediating Enhancer-Driven Transcription in Drosophila

Shidlovskii

Bylino

Шапошников

et al. 2021

IJMS

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The chromatin remodeler SWI/SNF is an important participant in gene activation, functioning predominantly by opening the chromatin structure on promoters and enhancers. Here, we describe its novel mode of action in which SWI/SNF factors mediate the targeted action of an enhancer. We studied the functions of two signature subunits of PBAP subfamily, BAP170 and SAYP, in Drosophila. These subunits were stably tethered to a transgene reporter carrying the hsp70 core promoter. The tethered subunits mediate transcription of the reporter in a pattern that is generated by enhancers close to the insertion site in multiple loci throughout the genome. Both tethered SAYP and BAP170 recruit the whole PBAP complex to the reporter promoter. However, we found that BAP170-dependent transcription is more resistant to the depletion of other PBAP subunits, suggesting that BAP170 may play a more critical role in establishing enhancer-dependent transcription.

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Section: Discussionmentioning

confidence: 84%

Subunits of the PBAP Chromatin Remodeler Are Capable of Mediating Enhancer-Driven Transcription in Drosophila

Shidlovskii

Bylino

Шапошников

et al. 2021

IJMS

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“…Binding sites for ZAD-C2H2 proteins are predominantly located in the region of active promoters [40,51,53,55]. It is assumed that they participate in the formation of open chromatin in the region of promoters and contribute to the recruitment of transcription factors that are not capable of binding with high specificity to DNA [39,56].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of CP190 Interaction with Architectural Proteins in Drosophila Melanogaster

Sabirov

Popovich

Boyko

et al. 2021

IJMS

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Most of the known Drosophila architectural proteins interact with an important cofactor, CP190, that contains three domains (BTB, M, and D) that are involved in protein–protein interactions. The highly conserved N-terminal CP190 BTB domain forms a stable homodimer that interacts with unstructured regions in the three best-characterized architectural proteins: dCTCF, Su(Hw), and Pita. Here, we identified two new CP190 partners, CG4730 and CG31365, that interact with the BTB domain. The CP190 BTB resembles the previously characterized human BCL6 BTB domain, which uses its hydrophobic groove to specifically associate with unstructured regions of several transcriptional repressors. Using GST pull-down and yeast two-hybrid assays, we demonstrated that mutations in the hydrophobic groove strongly affect the affinity of CP190 BTB for the architectural proteins. In the yeast two-hybrid assay, we found that architectural proteins use various mechanisms to improve the efficiency of interaction with CP190. Pita and Su(Hw) have two unstructured regions that appear to simultaneously interact with hydrophobic grooves in the BTB dimer. In dCTCF and CG31365, two adjacent regions interact simultaneously with the hydrophobic groove of the BTB and the M domain of CP190. Finally, CG4730 interacts with the BTB, M, and D domains of CP190 simultaneously. These results suggest that architectural proteins use different mechanisms to increase the efficiency of interaction with CP190.

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“…Transcription factors need to make physical contact with the transcription complex. This can only occur if the DNA strand between the promoter and a distal CRE loops out [11]. Theoretically, this principle would allow contacts between any CRE with any promoter, depending on the size of the loop.…”

Section: Basic Principles Of Gene Regulationmentioning

confidence: 99%

“…Such a pathological gain of regulatory activity is called "enhancer adoption" and can be found in rare developmental disorders [16]. The 3D structure may govern and orchestrate fundamental functional changes in cell biology like stem cell activation [11,17]. For more detailed information on the subject, we refer to excellent articles in this issue on osteoporosis, bone metabolism, and cancer-induced bone disease.…”

Section: Basic Principles Of Gene Regulationmentioning

confidence: 99%

“…By stabilizing such DNA loops, hub domains are created where, e. g., enhancers and promoters come close. The 3D structure may govern and orchestrate fundamental functional changes in cell biology like stem cell activation [11]. Regarding osteology, the best example may be CTCF-dependent vitamin-D-receptor signaling described in monocytes, implicating dynamic epigenetic changes of gene regulation in the context of nuclear receptor signaling [56].…”

Section: Three-dimensional Chromatin Organizationmentioning

confidence: 99%

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Epigenetics and Noncoding RNA – Principles and Clinical Impact

et al. 2021

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Genetics studies the inheritance of genetic information encoded by the base pair sequence and its variants. Sequence variants can have severe consequences as seen in genetically inherited diseases (e. g. osteogenesis Imperfecta, hypophosphatasia). On the other hand, epigenetics deals with inherited and dynamically reversible modifications of chromatin without changing the base pair sequence, resulting in a change in phenotype without a change in genotype. These modifications primarily exert their effects by influencing gene expression. Initially, the definition of epigenetics exclusively comprised inherited changes that persist across several generations without changes in the DNA sequence. This definition has been extended to include also dynamic and partially reversible changes that occur more short-term. These gene modulatory effects introduce new levels of complexity and are crucial determinants of cell fate and organismal development. With its length of approximately two meters, human DNA has to be compacted to fit into the nuclei and fulfill its functions. DNA is wrapped around histone octamers into so-called nucleosomes. DNA, histones, and other DNA-associated proteins together form what is called chromatin. DNA packaging is achieved by variable degrees of chromatin condensation depending on cell type and context. Epigenetic transcriptional regulation modifies the affinity and accessibility of cis-regulatory elements (CREs) for transcription factors and the basic transcriptional machinery and governs interaction between CREs. CREs include promoters, enhancers, silencers, and insulators and are potent modulators of gene expression impacting core cell biological processes such as proliferation and differentiation. Chromatin looping and remodeling by differential covalent modifications of DNA (e. g., methylation or hydroxylation) and histone tails (e. g., acetylation or methylation) elicit fundamental changes in CRE accessibility, thus impacting gene expression. Chromatin looping depends on a specialized machinery including cohesins. Chromatin modifications are mediated by specific enzymes like DNA methylases (DNMTs), histone-modifying enzymes, like histone methyl- and acetyltransferases (KMTs, HATs/KATs), and histone demethylases and deacetylases (KDMs, HDACs). It becomes increasingly evident that epigenetic (dys)regulation plays a decisive role in physiology and pathophysiology, impacting many age-related diseases like cancer and degenerative pathologies (e. g., osteoporosis, Alzheimer’s, or Parkinson’s) in a significant fashion. Recently, small-molecule inhibitors of chromatin-modifying enzymes (e. g., vorinostat) have been identified and successfully introduced in therapy. Significant progress in high-throughput sequencing technologies and big data analysis has broadened our understanding of noncoding (nc) RNAs and DNA sequence regions in (post-)transcriptional regulation and disease development. Among ncRNAs that play vital roles in gene expression are micro- (miRs) and long noncoding RNAs (lncRNAs; e. g., XIST or HOTAIR). By interacting with the coding genome, these RNAs modulate important genetic programs. Interfering RNAs can, for example, enhance the post-transcriptional degradation of transcripts, altering their translation, or assist in the recruitment of chromatin-modifying enzymes to regulate transcription. They can also be packaged into extracellular vesicles as cargo and thus deliver critical information to the microenvironment or even systemically to distant tissues. Therefore, ncRNAs represent a novel playground for therapeutical investigations and supplement epigenetic mechanisms of gene regulation while being subject to epigenetic regulation themselves. Last but not least, dysregulated ncRNAs can also propagate disease. Until recently, the detection of epigenetic phenomena necessitated invasive diagnostic interventions. However, with the arrival of so-called “liquid biopsies” an analysis of circulating cell-free DNA fragments (cfDNA) and RNAs as well as vesicle-packed RNAs through minimal invasively drawn blood samples can be obtained. Such “fragmentomics” and RNAomics approaches on peripheral blood will ultimately serve as diagnostic tools for personalized clinical interventions.

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Mechanisms of Enhancer-Promoter Interactions in Higher Eukaryotes

Cited by 50 publications

References 194 publications

Subunits of the PBAP Chromatin Remodeler Are Capable of Mediating Enhancer-Driven Transcription in Drosophila

Subunits of the PBAP Chromatin Remodeler Are Capable of Mediating Enhancer-Driven Transcription in Drosophila

Mechanisms of CP190 Interaction with Architectural Proteins in Drosophila Melanogaster

Epigenetics and Noncoding RNA – Principles and Clinical Impact

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