Question

The enhancers that are present near a gene are present in every cell in an organism, yet these enhancers can have tissue-specific effects on gene expression. Explain how enhancers could have tissue-specific effects on gene expression.

Answer 1

Enhancers increase transcription of genes which can be independent of location, distance and orientation with respect to gene promoters. Chromatin loops are formed that can bring the enhancers in close proximity with the promoter of the target genes. The enhancers act as sites for formation of pre-initiation complex of RNA polymerase and the transcription factors.

Many enhancers have sites for H3K4me1 and H3K27ac, as promoter markers. They may lack other markers such as H3K4me3 markers. Thus, they are subjected to methylation and acetylation of histone residues. These sites help to induce tissue specific expression of target genes. Super enhancer have H3K27ac sites can lead to binding of many different transcription factors. Super enhancers have been found in Klf4 and Esrrb genes. These super enhancers are regulated by environmental clues. Thus, they can be expressed at different levels in different cells. For example, some super enhancer show increased activity in conditions of pregnancy.

Enhancer RNA (eRNA) can act either directly or indirectly in gene expression. They can affect interactions between the enhancer and promoter via effects on pre-initiation complex, transcription binding sites on DNA or RNA. They can also act as co-factors for transcription factors that binds DNA or RNA. They are involved in formation of genomic loops between the enhancer and promoter, thereby either increasing transcription or inhibiting transcription.

Enhancer may be damaged by sequences such as AID (activation-induced cytidine deaminase). This has been seen in B cell development, where damaging loops can be formed between enhancer and promoter, affecting B cell function. Many long coding RNA (lncRNAs) known as x-eRNA were can be inhibited by RNA exosome that are present at super-enhancer. RNA exosome complexes are used to rapidly degrade DNA and cause genomic instability. Enhancer are known to protect against genomic instability by attaching to ssDNA. Insulator sequences may affect the interaction between enhancer and promoters, inhibiting the gene expression.

Long intergenic ncRNAs can be transcribed form enhancer. These ncRNAs can regulate expression of adjacent genes. They can target chromatin modifying factors that affect their interaction with the neighboring gene promoters. Recruitment of histone modifying complexes to promoters can be increase by FOSLI enhancer. These complexes are involved in release of RNA polymerase from promoter-proximal pausing. This leads to increased transcription from the promoter.