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Review
. 2020 Sep 30:8:592164.
doi: 10.3389/fcell.2020.592164. eCollection 2020.

The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1

Thijs C J Verheul  1 , Levi van Hijfte  2 , Elena Perenthaler  3 , Tahsin Stefan Barakat  3
Affiliations
Review

The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1

Thijs C J Verheul et al. Front Cell Dev Biol. .

Abstract

First described in 1991, Yin Yang 1 (YY1) is a transcription factor that is ubiquitously expressed throughout mammalian cells. It regulates both transcriptional activation and repression, in a seemingly context-dependent manner. YY1 has a well-established role in the development of the central nervous system, where it is involved in neurogenesis and maintenance of homeostasis in the developing brain. In neurodevelopmental and neurodegenerative disease, the crucial role of YY1 in cellular processes in the central nervous system is further underscored. In this mini-review, we discuss the various mechanisms leading to the transcriptional activating and repressing roles of YY1, including its role as a traditional transcription factor, its interactions with cofactors and chromatin modifiers, the role of YY1 in the non-coding genome and 3D chromatin organization and the possible implications of the phase-separation mechanism on YY1 function. We provide examples on how these processes can be involved in normal development and how alterations can lead to various diseases.

Keywords: YY1; enhancer; gene regulation; neurodevelopment; non-coding genome; non-coding regulatory element.

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Figures

FIGURE 1
FIGURE 1
Schematic diagram of human YY1 domains. Human YY1 is composed of 414 amino acids. It binds a small DNA sequence (5′-CCGCCATNTT-3′) through the four C2H2-type zinc fingers located at the C-terminal of the protein (amino acid 296–320, 325–347, 353–377, 383–407). The REPO domain (aa 201–226) and a glycine-lysine rich domain (GK-rich, aa 170–200) mediate transcriptional repression. The REPO domain is responsible for the interaction with polycomb group proteins while the GK rich domain with histone deacetylases (HDAC). The N-terminal region of the protein mediates transcriptional activation. It is composed mainly by acidic amino acids (aa 1–154) and by a stretch of 11 histidines (aa 70–80), that are thought to stimulate YY1 accumulation in nuclear speckles. In blue, the reported causative variants of Gabriele-de Vries syndrome are indicated.
FIGURE 2
FIGURE 2
Mechanism of transcriptional activation or repression by YY1. (A) YY1 can act as a traditional DNA-binding transcription factor interacting with an extensive list of co-factors that mediate the activation or repression of transcription. Some are listed in the figure. (B) YY1 can interact with chromatin remodeling complexes that regulate transcription by regulating chromatin accessibility. (C) YY1 regulates transcription via the formation of enhancer-promoter loops within larger TADs. The red ring represents Cohesin. (D) The phase separation model might also explain the activity of YY1 as a dynamic activator or repressor of transcription, based on the cocktail of co-factors present in the highly concentrated phase-separated droplets.
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