Biology subjects

Richter, H. J.

Publications and source records attributed to Richter, H. J..

3 recordsLinked to original sources

bioRxiv2026

Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERB. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPAR. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.

molecular biology↗

bioRxiv2025

The eukaryotic replisome intrinsically generates asymmetric daughter chromatin fibers

DNA replication is molecularly asymmetric, due to distinct mechanisms for lagging and leading strand DNA synthesis. Whether chromatin assembly on newly replicated strands is also asymmetric remains unknown, as visualizing this short-lived state in cells is impossible. To circumvent this limitation, we combine in vitro reconstitution of the Saccharomyces cerevisiae DNA and chromatin replication machineries with replication-aware single-molecule chromatin footprinting, to study how chromatin is re-assembled on replicated DNA. Leveraging the non-destructive, single-molecule, and strand-specific nature of our data, we discover an intrinsic asymmetry in nucleosome positioning patterns and organization between lagging- and leading-strand chromatin created by the yeast replisome. This asymmetry is only partially restored upon addition of chromatin assembly factors involved in de novo histone deposition and the ATP-dependent chromatin remodeler Isw1a, implying that other regulatory factors must resolve this asymmetry in cells. In sum, our data reveal the complexity of chromatin re-establishment following DNA replication, and suggest an asymmetric chromatin assembly intermediate on each daughter chromatid. These pathways have implications for essential chromatin-templated processes such as DNA repair, transcription, and gene silencing at replication forks.

biochemistry↗

bioRxiv2025

Pervasive and programmed nucleosome distortion patterns on single mammalian chromatin fibers

We present a genome-scale method to map the single-molecule co-occupancy of structurally distinct nucleosomes, subnucleosomes, and other protein-DNA interactions via long-read high-resolution adenine methyltransferase footprinting. Iteratively Defined Lengths of Inaccessibility (IDLI) classifies nucleosomes on the basis of shared patterns of intranucleosomal accessibility, into: i.) minimally-accessible chromatosomes; ii.) octasomes with stereotyped DNA accessibility from superhelical locations (SHLs) {+/-}1 through {+/-}7; iii.) highly-accessible unwrapped nucleosomes; and iv.) subnucleosomal species, such as hexasomes, tetrasomes, and other short DNA protections. Applying IDLI to mouse embryonic stem cell (mESC) chromatin, we discover widespread nucleosomal distortion on individual mammalian chromatin fibers, with >85% of nucleosomes surveyed displaying degrees of intranucleosomally accessible DNA. We observe epigenomic-domain-specific patterns of distorted nucleosome co-occupancy and positioning, including at enhancers, promoters, and mouse satellite repeat sequences. Nucleosome distortion is programmed by the presence of bound transcription factors (TFs) at cognate motifs; occupied TF binding sites are differentially decorated by distorted nucleosomes compared to unbound sites, and degradation experiments establish direct roles for TFs in structuring binding-site proximal nucleosomes. Finally, we apply IDLI in the context of primary mouse hepatocytes, observing evidence for pervasive nucleosomal distortion in vivo. Further genetic experiments reveal a role for the hepatocyte master regulator FOXA2 in directly impacting nucleosome distortion at hepatocyte-specific regulatory elements in vivo. Our work suggests extreme--but regulated--plasticity in nucleosomal DNA accessibility at the single-molecule level. Further, our study offers an essential new framework to model transcription factor binding, nucleosome remodeling, and cell-type specific gene regulation across biological contexts.

genomics↗