Search

In this Viewpoint article, experts provide their current opinions on heterochromatin definition, types and functional mechanisms.

Maria-Elena Torres-Padilla and colleagues use a targeted epigenomic approach to investigate the role of LINE-1 retroelements during early mouse development. Their data suggest that timely activation of LINE-1 regulates global chromatin accessibility and is integral to the mouse developmental program.

Nature Biotechnology asks a selection of researchers about the most exciting frontier in their field and the most needed technologies for advancing knowledge and applications.

Spatial genome organization into lamina-associated domains is first established in the mouse zygote immediately after fertilization without inheritance from the maternal germline—with the paternal and maternal pronucleus exhibiting different organization, which subsequently converges prior to implantation of the embryo.

Four studies detail changes in how DNA is wrapped around histone proteins and in molecular modifications to histones that occur after fertilization. The results shed light on the early regulation of gene expression. See Letters p.548, p.553 & p.558

Three studies highlight DUX proteins as key transcription factors regulating embryonic genome activation in early mammalian development.

Totipotent cells in mouse embryos and 2-cell-like cells have slow DNA replication fork speed. Perturbations that slow replication fork speed promote 2-cell-like cell emergence and improve somatic cell nuclear transfer reprogramming and formation of induced pluripotent stem cell colonies.

Rare cells resembling the 2-cell-stage embryo (2 C) arise in embryonic stem cell cultures. By performing single-cell analyses and an siRNA screen, the authors identify the intermediate cellular states and epigenetic regulators that underpin the transition to a 2C-like state.

Genome-wide replication timing maps of mouse embryos from the zygote to the blastocyst stage were generated using single-cell Repli-seq, shedding light on the establishment of the epigenome at the beginning of mammalian development.

Burton et al. show that H3K9me3 deposition catalysed by SUV39H2 and regulated by pericentromeric RNAs in the mouse paternal pronucleus does not suppress gene expression, but bookmarks promoters for compaction.

Lineage-specific gene expression programs in multicellular organisms are controlled by balanced ON and OFF signals, amongst which heterochromatin regulates expression by restricting activation cues. A study now provides insights into mammalian heterochromatin organisation, function and interplay with lineage-specific transcription factors.

Repetitive elements in differentiated cells are usually silenced. Genome-wide analyses in early mouse development show that repetitive-element expression decreases during development accompanied by the loss of active chromatin marks. LINE-1 and IAP retrotransposons become reactivated after fertilization, and LINE-1 transcription is regulated by short LINE-1 RNAs, which suggests that repetitive elements may be regulated through RNA during the earliest developmental stages.

High-throughput chemical screening identifies retinoic acid signaling as a regulatory pathway of 2-cell-like cell reprogramming and early mouse development.

Formerly regarded as ‘junk’ DNA, transposable elements are now thought to be players in genome evolution. A new study reveals remarkable conservation of a retrotransposon insertion acting as an alternative promoter to drive the expression of a cell cycle regulator isoform in early embryos, potentially controlling the timing of pre-implantation development.

Upon fertilization and during early mammalian development, major changes in cellular plasticity occur. This is accompanied by large-scale epigenome remodelling, as has been recently highlighted by the application of genomics techniques to this developmental period.

Liu, Xie and colleagues profile putative cis-regulatory elements in mouse oocytes and pre-implantation embryos. They further validate putative enhancers in oocytes and identify the transcription factors TCF3 and TCF12 as key regulators of folliculogenesis.

It is unclear how totipotent embryonic cells acquire their fate and what role chromatin dynamics have in this process. Technological advances in studying single cells have begun to improve our understanding of the mechanisms underlying lineage allocation and cell plasticity in early mammalian development.

Covalent histone modifications have been linked to many DNA processes. The repertoire of modifications is still growing, and histone H3K64 trimethylation is now shown to be localized to pericentric chromatin and its levels dynamically altered during developmental reprogramming in both embryos and primordial germ cells.

H3K64 trimethylation on the nucleosome lateral surface marks pericentric heterochromatin. Here Lange et al.show that H3K64me3 enrichment ensures heterochromatin integrity and occurs in an H3K9me3-dependent, but an H4K20me3- and heterochromatin protein 1-independent manner.

Polycomb Repressive Complex 2 (PRC2) plays critical roles in transcriptional silencing during development. Here the authors identify EZHIP as a cofactor of PRC2 expressed predominantly in the gonads, finding that EZHIP limits the enzymatic activity of PRC2 in germ cells in mice.

The role of different histone H3 variants following mouse fertilization has not been addressed. The histone H3.3, and its Lys 27 are involved in the establishment of paternal heterochromatin in the pericentric region of the mouse early embryo, through a mechanism involving dsRNA.

New data show that depletion of histone chaperone CAF-1 in mouse embryonic stem (ES) cells induces early embryonic-like cells that exhibit gene-expression patterns and reprogramming efficiencies characteristic of 2-cell-stage populations that arise spontaneously in ES-cell culture, thus suggesting that altered chromatin assembly contributes to differences in stem-cell plasticity.

It has been challenging to label endogenous genomic sequences in living cells, and this has limited attempts to study the dynamics of nuclear architecture in genome function. In a newly developed methodology, transcription activator–like effectors (TALEs) were used to label endogenous repetitive genomic sequences to visualize nuclear positioning and chromatin dynamics in cultured mouse cells and embryos.

Tight regulation of Nanog dose at the chromosome level is important for the acquisition of pluripotency during development.

The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe.