Summary The ability to measure human aging from molecular profiles has practical implications in many fields, including disease prevention and treatment, forensics, and extension of life. Although chronological age has been linked to changes in DNA methylation, the methylome has not yet been used to measure and compare human aging rates. Here, we build a quantitative model of aging using measurements at more than 450,000 CpG markers from the whole blood of 656 human individuals, aged 19 to 101. This model measures the rate at which an individual’s methylome ages, which we show is impacted by gender and genetic variants. Furthermore, we show that differences in aging rates help explain epigenetic drift and are reflected in the transcriptome. Our model highlights specific components of the aging process and provides a quantitative read-out for studying the role of methylation in age-related disease.

The heterogenic nature of troponin T (TnT) isoforms in fast skeletal and cardiac muscle suggests important functional differences. Dynamic features of rat cardiac TnT (cTnT) and rat fast skeletal TnT (fsTnT) reconstituted cardiac muscle preparations were captured by fitting the force response of small amplitude (0.5%) muscle length changes to the recruitment-distortion model. The recruitment of force-bearing cross-bridges (XBs) by increases in muscle length was favored by cTnT. The recruitment magnitude was approximately 1.5 times greater for cTnT- than for fsTnT-reconstituted muscle fibers. The speed of length-mediated XB recruitment (b) in cTnT-reconstituted muscle fiber was 0.50-0.57 times as fast as fsTnT-reconstituted muscle fibers (3.05 vs. 5.32 s(-1) at sarcomere length, SL, of 1.9 microm and 4.16 vs. 8.36 s(-1) at SL of 2.2 microm). Due to slowing of b in cTnT-reconstituted muscle fibers, the frequency of minimum stiffness (f(min)) was shifted to lower frequencies of muscle length changes (at SL of 1.9 microm, 0.64 Hz, and 1.16 Hz for cTnT- and fsTnT-reconstituted muscle fibers, respectively; at SL of 2.2 microm, 0.79 Hz, and 1.11 Hz for cTnT- and fsTnT-reconstituted muscle fibers, respectively). Our model simulation of the data implicates TnT as a participant in the process by which SL- and XB-regulatory unit cooperative interactions activate thin filaments. Our data suggest that the amino-acid sequence differences in cTnT may confer a heart-specific regulatory role. cTnT may participate in tuning the heart muscle by decreasing the speed of XB recruitment so that the heart beats at a rate commensurate with f(min).

The 4D organization of the interphase nucleus, or the 4D Nucleome (4DN), reflects a dynamical interaction between 3D genome structure and function and its relationship to phenotype. We present initial analyses of the human 4DN, capturing genome-wide structure using chromosome conformation capture and 3D imaging, and function using RNA-sequencing. We introduce a quantitative index that measures underlying topological stability of a genomic region. Our results show that structural features of genomic regions correlate with function with surprising persistence over time. Furthermore, constructing genome-wide gene-level contact maps aided in identifying gene pairs with high potential for coregulation and colocalization in a manner consistent with expression via transcription factories. We additionally use 2D phase planes to visualize patterns in 4DN data. Finally, we evaluated gene pairs within a circadian gene module using 3D imaging, and found periodicity in the movement of clock circadian regulator and period circadian clock 2 relative to each other that followed a circadian rhythm and entrained with their expression.4D Nucleome | networks | Laplacian | interphase nucleus | phase plane

Bipolar disorder (BP) is a chronic psychiatric condition characterized by dynamic, pathological mood fluctuations from mania to depression. To date, a major challenge in studying human neuropsychiatric conditions such as BP has been limited access to viable central nervous system tissue to examine disease progression. Patient-derived induced pluripotent stem cells (iPSCs) now offer an opportunity to analyze the full compliment of neural tissues and the prospect of identifying novel disease mechanisms. We have examined changes in gene expression as iPSC derived from well-characterized patients differentiate into neurons; there was little difference in the transcriptome of iPSC, but BP neurons were significantly different than controls in their transcriptional profile. Expression of transcripts for membrane bound receptors and ion channels was significantly increased in BP-derived neurons compared with controls, and we found that lithium pretreatment of BP neurons significantly altered their calcium transient and wave amplitude. The expression of transcription factors involved in the specification of telencephalic neuronal identity was also altered. Control neurons expressed transcripts that confer dorsal telencephalic fate, whereas BP neurons expressed genes involved in the differentiation of ventral (medial ganglionic eminence) regions. Cells were responsive to dorsal/ventral patterning cues, as addition of the Hedgehog (ventral) pathway activator purmorphamine or a dorsalizing agent (lithium) stimulated expression of NKX2-1 (ventral identity) or EMX2 (dorsal) in both groups. Cell-based models should have a significant impact on our understanding of the genesis and therefore treatment of BP; the iPSC cell lines themselves provide an important resource for comparison with other neurodevelopmental disorders.