Molecular signals of epigenetic states

Abstract

Epigenetic signals are responsible for the establishment, maintenance, and reversal of metastable transcriptional states that are fundamental for the cell's ability to "remember" past events, such as changes in the external environment or developmental cues. Complex epigenetic states are orchestrated by several converging and reinforcing signals, including transcription factors, noncoding RNAs, DNA methylation, and histone modifications. Although all of these pathways modulate transcription from chromatin in vivo, the mechanisms by which epigenetic information is transmitted through cell division remain unclear. Because epigenetic states are metastable and change in response to the appropriate signals, a deeper understanding of their molecular framework will allow us to tackle the dysregulation of epigenetics in disease.

Figure 1. Cis and trans epigenetic signals

(A) A trans epigenetic signal (yellow circle) is transmitted by partitioning of the cytosol during cell division and maintained by feedback loops. As an example here we depict a simple regulatory loop in which the epigenetic signal induces its own expression. (B) Cis signals (yellow flag) are molecular signature physically associated with the DNA and inherited via chromosome segregation during cell division.

Figure 2. RNA-directed deposition of epigenetic signals

(A-C) Sequence-specific recognition models for both sRNAs (depicted) and lncRNAs. (A) Interaction of an sRNA with complementary sequences on a nascent transcriptl. (B) Interaction of an sRNA with ssDNA to form a heteroduplex. (C) Recognition of sequence motifs by sRNA in a closed dsDNA duplex. (D-E) additional recruitment models for lncRNAs. (D) A folded lncRNA recognizes a DNA sequence via complex surface-mediated interactions. (E) A lncRNA acting locally in a co-transcriptional fashion by being anchored to chromatin by RNA PII. RBP, RNA binding protein; A, hypothetical adaptor protein; CMC, chromatin-modifying complex.

Figure 3. Transmission of epigenetic states

(A) Transmission of DNA methylation patterns after DNA replication. (B) Hypothetical model for the maintenance of a histone-associated epigenetic signal, using H3K27me3 (yellow flag) as an example. H3K27me3 is diluted during DNA replication by the deposition of unmodified octamers. Binding of EED to H3K27me3 stimulates the enzymatic activity of EZH2, which places more H3K27me3 marks on neighboring nucleosomes, thus restoring a full epigenetic signature on both chromatids (48). (C) Maintenance of a chromatin domain via a “secondary” signal. S phase transcription of heterochromatic repeats in S. pombe generates sRNA species that recruit chromatin-modifying complexes to reestablish heterochromatic signatures at the target loci.