Ectopic resurrection of embryonic/developmental genes in aging

Development and aging are key life stages of an organ-ism. During the development phase, stem cells are highly active, contributing to embryogenesis and organismal growth via lineage commitment. By contrast, the viability and function of stem cells and terminally differentiated cells markedly diminish in most tissues during aging

Development and aging are key life stages of an organism. During the development phase, stem cells are highly active, contributing to embryogenesis and organismal growth via lineage commitment. By contrast, the viability and function of stem cells and terminally differentiated cells markedly diminish in most tissues during aging. Epigenetic regulation plays a critical role in these cell fate determination processes, including stem cell differentiation and cellular aging.

Building epigenetic circuitry to activate lineage-appropriate genes during differentiation
Emerging studies have proved that epigenetic properties (including histone modifications, chromatin accessibility, and DNA methylation) play critical roles in regulating transcription programs for lineage specification (Hawkins et al. 2010;Xie et al. 2013;Zhang et al. 2019). Among them, the nuclear radial repositioning of chromatin is indispensable in regulating the transcription of genes that are important for cellular identity and function during lineage commitment. As determined by the DNA adenine methyltransferase identification (DamID) assay, the sequester and release of specific genomic loci from the nuclear lamina (NL) are important for transcriptional regulation during the differentiation processes. In the differentiation processes from mouse embryonic stem cells to lineage-committed neural precursor cells (NPCs), the gain of association of some "stemness" genes, such as Nanog, Klf4, and Oct4, with NL is concomitant with their silenced transcription, whereas neuronal and cell-cycle genes disassociated from the NL are activated (Peric-Hupkes et al. 2010). In the differentiation processes from NPCs to astrocytes, cell-cycle genes are sequestered to the NL and thus silenced (Peric-Hupkes et al. 2010). Consistently, by decoding large-scale epigenomic datasets, including R-loops, histone modifications, DNA methylation, and chromatin accessibility, Yan et al. reported that the gain of the NL associations for R-loop-associated repressed Polycomb regions (decorated with R-loops and histone modification H3K27me3) is associated with the silence of core pluripotent genes (such as NANOG) and lineage-inappropriate genes in human stem cell differentiation (Yan et al. 2020) (Fig. 1).
Altogether, these data suggest that human embryonic stem cells (hESCs) show high plasticity to differentiate into functionally specialized cell types. Cell differentiation is a process of establishing epigenetic circuitry to activate the expression of housekeeping genes and celltype-specific genes that confer critical and specialized functions and viability to these differentiated cells (Fig. 1).

Eroded epigenetic circuitry induces activation of lineage-inappropriate genes during aging
Aging is characterized by functional declines with age, which is a key risk factor driving chronic diseases. The loss of core components of nuclear meshwork and the

Open Access
Current Medicine and DNA accessibility) synergistically lead to ectopic expression of developmentally restricted genes, e.g., a cluster of pregnancy-specific beta-1 glycoprotein (PSG) genes that are specifically expressed in the syncytiotrophoblast of the placenta during pregnancy, and trigger stem cell aging. Further metadata analyses and experimental verifications demonstrate that PSGs serve as novel biomarkers of human organismal aging and potential drivers in cellular and tissue aging ( Fig. 1) . Consistent with this study, similar activation of lineage-inappropriate genes has been reported in senescent human diploid fibroblasts (Tomimatsu et al. 2022). The derepression of heterochromatin region is associated with the leakage expression of lineage-inappropriate genes, including LCE2 genes that are preferentially expressed in keratinocytes of skin/epidermis and NLRP3 that is predominantly expressed in macrophages (Tomimatsu et al. 2022). Similarly, the important role of the nuclear lamina Fig. 1 Schematic diagram showing the epigenomic dynamics and transcriptional changes during differentiation and senescence. During differentiation, epigenetic circuitry is established to activate lineage-appropriate genes and repress pluripotent genes. During senescence, the eroded epigenetic circuitry aberrantly activates lineage-inappropriate genes that promote senescence and serve as biomarkers of aging in repressing lineage-inappropriate genes has also been reported in Drosophila (Vergnes et al. 2004). The nuclear lamina (B-type lamin) is indispensable for the repression of testis-specific gene clusters in somatic tissues of Drosophila (Vergnes et al. 2004). Depletion of B-type lamin results in the detachment of testis-specific clusters from the NL, resulting in the transcriptional activation of those testis-specific genes in somatic cells (Vergnes et al. 2004). Nuclear lamina proteins also play the guardian roles for epigenome identity and transcription fidelity in post-mitotic cells (Shah et al. 2021). Cardiomyocytes derived from human induced pluripotent stem cells (hiP-SCs) harboring pathogenic LMNA variants of dilated cardiomyopathy (DCM) show disrupted nuclear morphology and aberrant organization of peripheral chromatin, which is associated with the aberrantly activated expression of non-myocyte lineage genes in DCM cardiomyocytes (Shah et al. 2021). These data demonstrate that the nuclear lamina network safeguards the cellular identity via regulating the expression of functional genes. Therefore, the loss of the structure restrains caused by the declined nuclear lamina components and disrupted nuclear shapes in senescent or malfunctioned cells are linked to epigenome erosion and the misexpression of genes that are normally expressed in other lineages ( Fig. 1) . The epigenomic dynamics also contribute to the aberrant transcriptional events in the genomic "dark matter" during aging. In senescent hMSCs, specific epigenetic alterations, manifested by the loss of heterochromatic marks and the DNA hypomethylation, unlock human endogenous retroviruses K (HERVK), leading to the formation of retrovirus-like particles that confer a senescence phenotype to young cells (Liu et al. 2021). Intriguingly, ERV elements have been reported to be activated during human embryonic development (Chuong 2018;Grow et al. 2015;Xie et al. 2013;Zhang et al. 2019). Specifically, ERV elements are activated in the placenta and are crucial for the differentiation of cytotrophoblast to syncytiotrophoblast during pregnancy (Chuong 2018). In addition, the expression of ERV elements is detected in human blastocysts or hESCs (Grow et al. 2015;Xie et al. 2013;Yan et al. 2020;Zhang et al. 2019). These studies indicate that ectopic resurrection of developmentally restricted repetitive elements (REs) / endogenous retrovirus is a hallmark and driving force of cellular, organic, and organismal aging (Fig. 1) (Liu et al. 2021;. In conclusion, these observations provide novel insights into the epigenetic mechanisms of aging regulation. Specifically, the eroded epigenetic circuitry (including increased epigenetic entropy and loss of epigenetic polarity and identity) can activate the lineage-inappropriate genes and REs, thereby driving aging. Thus, we hypothesized that the "Ectopic Resurrection of Developmental or Embryonic genes" (ERODE) is a hallmark of aging. These findings strengthen the notion that the stability of the nuclear structure is fundamental to cellular functions. In the future, an in-depth survey of the dynamics of core nuclear structure components/condensates (such as the nuclear lamina, nuclear speckle, paraspeckle, nucleolus, and Polycomb repressive complexes) during aging will help to advance our understanding of the structural basis for maintaining the epigenomic identity and stability and guarding the precision of transcription, identify the biomarkers or driving factors of aging, and develop clinical interventions that can alleviate human aging and aging-associated disorders.