Biology subjects

Lou, T.

Publications and source records attributed to Lou, T..

6 recordsLinked to original sources

bioRxiv2025

Complete and haplotype-resolved maps of genomic and epigenetic discordance in monozygotic twins

Telomere-to-telomere (T2T) genome assemblies are indispensable for accurate detection of genetic variation and for resolving complex repetitive regions. Monozygotic (MZ) twin pedigrees provide a powerful model to investigate de novo mutations (DNMs), however, comprehensive, haplotype-resolved analyses of structural variation (SV), allele-specific inheritance in complex regions, and DNA methylation in diploid human genomes remain limited. Here, we generated complete, haplotype-resolved T2T assemblies for two female twins (C33 and C35) from a Han Chinese pedigree by integrating complementary, state-of-the-art sequencing technologies. The resulting T2T-C33 and T2T-C35 assemblies are highly contiguous and complete, with Genome Continuity Inspector (GCI) scores of 74.94 (maternal) and 77.94 (paternal), and consensus quality values (QV) >75 (k = 21). We comprehensively cataloged 62 inter-twin single-nucleotide variants (SNVs), 15 small indels, and identified both shared and private DNMs, revealing nascent genomic divergence between the MZ twins. Focused interrogation of complex regions uncovered pronounced haplotype-specific length polymorphisms and structural heterogeneity within centromeric higher-order repeat (HOR) arrays. Notably, we observed extensive HOR copy-number variation between haplotypes, including a large copy-number difference on maternal chromosome 18, underscoring dynamic HOR array evolution even among genetically identical individuals. Concurrently, genome-wide DNA methylation profiling delineated allele-specific epigenetic variation that may contribute to phenotypic discordance. Together, these high-quality, diploid T2T genomes from a Han Chinese pedigree provide a valuable resource for population-aware genomics and reveal fine-scale, haplotype-specific divergence in MZ twins. Our results advance understanding of repeat dynamics, centromeric architecture, epigenetic variation and the spectrum of human genomic variation at single-base and structural scales.

genomics↗

bioRxiv2025

Cortex-Wide Substrates for Body Schema and Action Awareness

The concept of the body schema originated from studies of patients with cortical lesions who were unable to localize their body parts in space or perceive passive movements (Head & Holmes, 1911). Current consensus defines the body schema as the brains internal representation of the body configuration in space used for both embodied perception and voluntary action (de Vignemont, 2010; Berlucchi & Aglioti, 2010; Vallar et al., 2025). Despite extensive research, how the cortex efficiently encodes the vast repertoire of body postures to support natural behavior remains poorly understood. Here, we reveal the representational format underlying the body schema by combining large-scale electrophysiological recordings with full-body 3D tracking and joint angle computation in freely behaving mice. Across cortical regions, neurons encoded diverse postural features in distinct reference frames: posterior parietal cortex (PPC) populations preferentially encoded body midline-referenced features, while sensorimotor cortices utilized a gravity-referenced frame. Strikingly, during performance of different stereotyped actions, distinct cortical ensembles were selectively activated. These action ensembles fired in phase-locked sequences that tiled the full action cycle, providing a neural substrate for action awareness. A network model recapitulated these dynamics and identified low-dimensional action subspaces within population activity. Together, these findings reveal that the cortex organizes the body schema around actions, compressing high-dimensional kinematics into an efficient, body-midline-and gravity-anchored, action-aware neural code.

neuroscience↗

bioRxiv2023

Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1

The intricate regulation of chromatin plays a key role in controlling genome architecture and accessibility. Histone lysine methyltransferases regulate chromatin by catalyzing the methylation of specific histone residues but are also hypothesized to have equally important non-catalytic roles. SUV420H1 di- and tri-methylates histone H4 lysine 20 (H4K20me2/me3) and plays crucial roles in DNA replication, repair, and heterochromatin formation, and is dysregulated in several cancers. Many of these processes were linked to its catalytic activity. However, deletion and inhibition of SUV420H1 have shown distinct phenotypes suggesting the enzyme likely has uncharacterized non-catalytic activities. To characterize the catalytic and non-catalytic mechanisms SUV420H1 uses to modify chromatin, we determined cryo- EM structures of SUV420H1 complexes with nucleosomes containing histone H2A or its variant H2A.Z. Our structural, biochemical, biophysical, and cellular analyses reveal how both SUV420H1 recognizes its substrate and H2A.Z stimulates its activity, and show that SUV420H1 binding to nucleosomes causes a dramatic detachment of nucleosomal DNA from histone octamer. We hypothesize that this detachment increases DNA accessibility to large macromolecular complexes, a prerequisite for DNA replication and repair. We also show that SUV420H1 can promote chromatin condensates, another non-catalytic role that we speculate is needed for its heterochromatin functions. Together, our studies uncover and characterize the catalytic and non-catalytic mechanisms of SUV420H1, a key histone methyltransferase that plays an essential role in genomic stability.

biochemistry↗

bioRxiv2023

ErbB inhibition impairs cognition via disrupting myelination and aerobic glycolysis in oligodendrocytes

White matter abnormalities are an emerging feature of schizophrenia, yet the underlying pathophysiological mechanisms are largely unknown. Disruption of ErbB signaling that is essential for peripheral myelination has been genetically associated with schizophrenia and white matter lesions in schizophrenic patients. However, the roles of ErbB signaling in oligodendrocytes remain elusive. Here, we used a pan-ErbB inhibition strategy and demonstrated the synergistic functions of endogenous ErbB receptors in oligodendrocytes. Through analyses of the cellular, histological, biochemical, behavioral, and electrophysiological differences in mice with manipulation of ErbB activities in oligodendrocytes at different differentiation stages, we found that ErbB signaling regulates myelination and aerobic glycolysis in oligodendrocytes, and both functions are required for working memory. ErbB inhibition in oligodendrocytes at early differentiation stages induces hypomyelination by suppressing the differentiation of newly-formed oligodendrocytes. In contrast, ErbB inhibition in mature oligodendrocytes alters neither myelination nor oligodendrocyte numbers, but accelerates axonal conduction decline under energy stress. Mechanistically, mature oligodendrocytes with ErbB inhibition reduce the expression of lactate dehydrogenase A, failing to provide lactate to electrically active axons. Supplementation of L-lactate restores axonal conduction and working memory capacity that are suppressed by ErbB inhibition in mature oligodendrocytes. These findings reveal the indispensable roles of ErbB signaling in white matter integrity and function, and provide insights into the multifaceted contributions of white matter abnormalities to cognitive impairment.

neuroscience↗

bioRxiv2022

Assessing base-resolution DNA mechanics on the genome scale

Intrinsic DNA properties such as bending play a crucial role in diverse biological systems. A recent advantage in the high-throughput method called loop-seq makes it possible to determine bendability of hundred thousand 50-bp DNA duplexes in one experiment. However, its still infeasible to assess whole sequence bendability in large genomes such as human, which needs thousands of loop-seq experiments. Here we introduce BendNet - a neural network to accurately predict the intrinsic DNA bending at base-resolution by only given DNA sequences. BendNet can increase the resolution of experimental results, and can predict DNA bendability for any new given sequences in high accuracy. We applied BendNet to the human genome and observed high-stiffness regions located at both transcriptional start sites and transcriptional end sites. Such stiffness patterns are different for coding and non-coding genes, which matches distinct nucleosome occupancy patterns. As expected, most transcription factors (TFs) bind in DNA of low bendability. In contrast, we observed an unusually high bendability within binding elements of specific TFs such as EBF1 and regulators of genome folding such as CTCF. These factors either co-bind or compete with nucleosomes to carry out their functions. More interestingly, CTCF binding regions exhibit the highest bendability than other DNA elements, implying their potential role in trapping and holding the CTCF in the exact locations to make sure CTCF as stable anchor in loop extrusion process. Our work provides a tool to assess DNA bendability for large-scale DNA sequences and expands our understanding on DNA mechanics in chromatin regulation and genome folding.

genomics↗

bioRxiv2021

In Diverse Conditions Intrinsic Chromatin Condensates Have Liquid-like Material Properties

Eukaryotic nuclear DNA is wrapped around histone proteins to form nucleosomes, which further assemble to package and regulate the genome. Understanding of the physical mechanisms that contribute to higher order chromatin organization is limited. Previously, we reported the intrinsic capacity of chromatin to undergo phase separation and form dynamic liquid-like condensates, which can be regulated by cellular factors. Recent work from Hansen, Hendzel, and colleagues suggested these intrinsic chromatin condensates are solid in all but a specific set of conditions. Here we show that intrinsic chromatin condensates are fluid in diverse solutions, without need for specific buffering components. Exploring experimental differences in sample preparation and imaging between these two studies, we suggest what may have led Hansen, Hendzel, and colleagues to mischaracterize the innate properties of chromatin condensates. We also describe how liquid-like in vitro behaviors can translate to the locally dynamic but globally constrained movement of chromatin in cells.

biophysics↗