Epigenomes

Prevailing models of neurodegeneration center on amyloid-$\beta$ and tau, yet metabolic dysfunction precedes proteinopathy by decades. We propose compartment-specific citrate uncoupling: opposing disturbances of citrate in neurons and astrocytes as a proteinopathy-independent driver of neurodegeneration. In neurons, a Warburg-like shift depletes cytosolic citrate, which starves ATP-citrate lyase (ACLY) and erodes the H3K27ac/H3K9ac marks that sustain synaptic gene expression, while loss of citrate-mediated PFK1 inhibition collapses the SLC13A5-dependent glycolytic gate. In surviving astrocytes, loss of ACO1, with SLC13A3 a weaker and less specific accompaniment, traps newly synthesized citrate intracellularly; ACLY then hyper-activates and STAT3 hyperacetylation drives an A1 identity. The intercellular citrate gradient inverts. We reanalyzed GSE5281 (161 postmortem samples across six brain regions). Core TCA-cycle enzymes were coherently downregulated in Alzheimer’s disease in five of six regions, more strongly in women, and not in the disease-spared visual cortex. The SLC13 transporter family instead shifted in opposite directions across regions. A cell-type-resolved reanalysis of the SEA-AD multiregion atlas placed the astrocytic arm on ACO1, which fell with pseudo-progression in all nine regions tested; SLC13A3 fell across most cortical cell types and is not compartment-specific. A four-proposition framework then combines PDK1 induction, Cryo-NanoSIMS, MALDI-TIMS-MSI, and spatial transcriptomics. If the model holds, neurodegeneration reads as a routing failure of a central metabolic hub.

Background/Objectives: Forensic epigenetics complements DNA profiling by informing donor age and trace origin, but technical promise does not establish casework validity. We mapped applications and validation evidence. Methods: Scopus, PubMed/MEDLINE and Web of Science were searched through 15 June 2026. Empirical reports were assigned a dominant application and an author-defined C1–C5 evidence category (not a readiness score). Results: Of 596 assessed full texts, 338 entered the evidence map (322 empirical studies and 16 contextual records). Among studies, 312/322 (96.9%) fell within C1–C3, 10 were C4 and none met the C5 definition of documented routine implementation in the indexed and retrievable corpus. C4 records advanced evaluation designs, which may reveal unsuccessful transfer or unresolved bias rather than acceptable casework performance. Age estimation (177 studies) and body-fluid/tissue identification (92) accounted for all C4 evidence. Of 272 identifiable methylation workflows, chemical conversion predominated; 23 studies were non-methylation, 26 reused methylation data without a new assay and one workflow remained unresolved. Conclusions: Published evidence is substantial but heterogeneous; internal performance cannot substitute for independent validation, inter-laboratory reproducibility, calibrated uncertainty, laboratory-specific procedures, controlled reporting and proportionate governance. Study-level counts do not quantify the proportion of distinct validated methods or establish absence of unindexed operational use.

Preterm birth (PTB) remains a leading cause of neonatal morbidity and mortality worldwide, with limited tools for early prediction or targeted prevention. Increasing evidence identifies the placenta as a central regulator of gestational duration, and alterations in placental gene regulatory programs have been associated with PTB. This review synthesizes recent advances in placental genomics and epigenomics, emphasizing how cell-type-specific regulatory landscapes shape PTB risk. We describe how DNA methylation, chromatin accessibility, and transcriptional heterogeneity across trophoblasts, Hofbauer cells, endothelial cells, Natural Killer (NK) cells, and mesenchymal stromal cells integrate maternal, fetal, immune, and environmental signals. We further evaluate emerging liquid biopsy approaches, focusing on circulating cell-free placental DNA (cfpDNA) methylation as a minimally invasive strategy to detect placental dysfunction. Single-cell and long-read sequencing technologies have enabled high-resolution mapping of placental regulatory architecture, revealing cell-type-specific pathways underlying inflammation, impaired trophoblast differentiation, and aberrant vascular remodeling. These studies support the investigation of placental epigenetic alterations as potential contributors to PTB-associated biology, although their causal roles and consistency across PTB subtypes remain uncertain. Circulating cfpDNA methylation profiles are being investigated as minimally invasive indicators of placental biology, but their accuracy and clinical utility for PTB prediction require further validation. Together, these findings suggest that epigenomic alterations may be associated with biological pathways implicated in PTB and may also provide measurable molecular signatures in maternal circulation.