The power of the (imperfect) palindrome: Sequence‐specific roles of palindromic motifs in gene regulation

Abstract

In human languages, a palindrome reads the same forward as backward (e.g., 'madam').In regulatory DNA, a palindrome is an inverted sequence repeat that allows a transcription factor to bind as a homodimer or as a heterodimer with another type of transcription factor. Regulatory palindromes are typically imperfect, that is, the repeated sequences differ in at least one base pair, but the functional significance of this asymmetry remains poorly understood. Here, we review the use of imperfect palindromes in Drosophila photoreceptor differentiation and mammalian steroid receptor signaling. Moreover, we discuss mechanistic explanations for the predominance of imperfect palindromes over perfect palindromes in these two gene regulatory contexts. Lastly, we propose to elucidate whether specific imperfectly palindromic variants have specific regulatory functions in steroid receptor signaling and whether such variants can help predict transcriptional outcomes as well as the response of individual patients to drug treatments.

Unraveling the palindromic and nonpalindromic motifs of retroviral integration site sequences by statistical mixture models

“…Given the symmetry of retroviral intasome, the existence of nonpalindromic submotifs is an interesting feature of the tDNA sequences. Imperfect palindromes are known to regulate the binding of transcription factors, where changes in one half-site affect the binding of the transcription factor to the other half-site of the motif ( Datta and Rister 2022 ). Unlike the motifs of transcription factors, retroviral IS motifs are limited to a few positions and are probably not the consequence of the sequence-specific IN–tDNA interactions.…”

“…Given the symmetry of IN multimers, the preference for palindromic motifs may be expected. In addition, the palindromic motif is observed at target sites of other transposable elements ( Vigdal et al 2002 ; Miyao et al 2003 ; Linheiro and Bergman 2008 ; Gangadharan et al 2010 ; Mularoni et al 2012 ; Riggs et al 2021 ) and is a marker of binding sites of some transcription factors ( Datta and Rister 2022 ).…”

Unraveling the Palindromic and Non-Palindromic Motifs of Retroviral Integration Site Sequences by Statistical Mixture Models

“…Given the symmetry of retroviral intasome, the existence of non-palindromic sub-motifs is an interesting feature of the tDNA sequences. Imperfect palindromes are known to regulate the binding of transcription factors where changes in one half-site affect the binding of the transcription factor to the other half-site of the motif 45 . Unlike the motifs of transcription factors, retroviral IS motifs are limited to a few positions and are probably not the consequence of the sequence-specific IN-tDNA interactions.…”

“…Given the symmetry of IN multimers, the preference for palindromic motifs may be expected. In addition, the palindromic motif is observed at target sites of other transposable elements [39][40][41][42][43][44] and is a marker of binding sites of some transcription factors 45 .…”

Transcriptional precision in photoreceptor development and diseases – Lessons from 25 years of CRX research

“…DNA binding specificity is one important mechanism that transcription factors evolve to achieve functional specificity such that genes with even a slight difference in DNA motif in their regulatory regions can respond differently to changing compositions of transcription factors and drive distinct phenotypic outcomes during development. One remarkable example is an 11bp activator homeodomain motif, either in the palindromic version, regulates phototransduction genes that are expressed broadly in all photoreceptors; or when exhibiting unique single base pair substitutions, restrict D. melanogaster rhodopsin genes to be expressed in subsets of photoreceptors ( Rister et al, 2015 ; Poupault et al, 2021 ; Datta and Rister, 2022 ). These seemingly “trivial” differences in the 11bp palindromic motifs coordinate a broad spectrum of homeodomain proteins of different DNA binding specificity and transactivation activity in the developing photoreceptors ( Tahayato et al, 2003 ; Mishra et al, 2010 ; Johnston et al, 2011 ).…”