Biology subjects

Huang, W.-C.

Publications and source records attributed to Huang, W.-C..

4 recordsLinked to original sources

bioRxiv2020

Expanding diversity of Asgard archaea and the elusive ancestry of eukaryotes

Comparative analysis of 162 (nearly) complete genomes of Asgard archaea, including 75 not reported previously, substantially expands the phylogenetic and metabolic diversity of the Asgard superphylum, with six additional phyla proposed. Phylogenetic analysis does not strongly support origin of eukaryotes from within Asgard, leaning instead towards a three-domain topology, with eukaryotes branching outside archaea. Comprehensive protein domain analysis in the 162 Asgard genomes results in a major expansion of the set of eukaryote signature proteins (ESPs). The Asgard ESPs show variable phyletic distributions and domain architectures, suggestive of dynamic evolution via horizontal gene transfer (HGT), gene loss, gene duplication and domain shuffling. The results appear best compatible with the origin of the conserved core of eukaryote genes from an unknown ancestral lineage deep within or outside the extant archaeal diversity. Such hypothetical ancestors would accumulate components of the mobile archaeal eukaryome via extensive HGT, eventually, giving rise to eukaryote-like cells.

genomics↗

bioRxiv2020

Inhibition of SARS-CoV-2 viral entry in vitro upon blocking N- and O-glycan elaboration

The Spike protein of SARS-CoV-2, its receptor binding domain (RBD), and its primary receptor ACE2 are extensively glycosylated. The impact of this post-translational modification on viral entry is yet unestablished. We expressed different glycoforms of the Spike-protein and ACE2 in CRISPR-Cas9 glycoengineered cells, and developed corresponding SARS-CoV-2 pseudovirus. We observed that N- and O-glycans had only minor contribution to Spike-ACE2 binding. However, these carbohydrates played a major role in regulating viral entry. Blocking N-glycan biosynthesis at the oligomannose stage using both genetic approaches and the small molecule kifunensine dramatically reduced viral entry into ACE2 expressing HEK293T cells. Blocking O-glycan elaboration also partially blocked viral entry. Mechanistic studies suggest multiple roles for glycans during viral entry. Among them, inhibition of N-glycan biosynthesis enhanced Spike-protein proteolysis. This could reduce RBD presentation on virus, lowering binding to host ACE2 and decreasing viral entry. Overall, chemical inhibitors of glycosylation may be evaluated for COVID-19.

biochemistry↗

bioRxiv2020

Dopa decarboxylase is a genetic hub of parental control over offspring behavior

Dopa decarboxylase (DDC) regulates the synthesis of monoaminergic neurotransmitters and is linked to psychiatric and metabolic disorders. Ddc exhibits complex genomic imprinting effects that have not been functionally studied. Here, we investigate different noncanonical imprinting effects at the cellular level with a focus on Ddc. Using allele-specific reporter mice, we found Ddc exhibits dominant expression of the maternal allele in subpopulations of cells in 14 of 52 brain regions, and dominant paternal or maternal allele expression in adrenal cell subpopulations. Maternal versus paternal Ddc allele null mutations differentially affect offspring social, foraging and exploratory behaviors. Machine learning analyses of naturalistic foraging in Ddc-/+ and +/- offspring uncovered finite behavioral sequences controlled by the maternal versus paternal Ddc alleles. Additionally, parental Ddc genotype is revealed to affect behavior independent of offspring genotype. Thus, Ddc is a hub of maternal and paternal influence on behavior that mediates diverse imprinting and parental effects. HIGHLIGHTSO_LIDopa decarboxylase (Ddc) allelic expression resolved at the cellular level C_LIO_LICells differentially express maternal versus paternal Ddc alleles C_LIO_LIMaternal and paternal Ddc alleles control distinct behavioral sequences C_LIO_LIParental Ddc genotype affects offspring independent of mutation transmission C_LI eTOCAllelic reporter mice and machine learning analyses reveal dopa decarboxylase is affected by diverse imprinting and parental effects that shape finite behavioral sequences in sons and daughters.

neuroscience↗

bioRxiv2020

Probing the functions of microglial cyclin-dependent kinase 5 under physiological and pathological conditions

Cyclin dependent kinase 5 (Cdk5) regulates various developmental and physiological processes in the central nervous system. Deregulation of Cdk5 activity in neurons induces severe neurodegeneration and has been implicated in Alzheimers disease (AD) and other neurodegenerative conditions. A large fraction of AD risk genes are highly expressed in microglia, highlighting an important role for these cells in AD pathogenesis. While Cdk5 function in neurons is well characterized, our understanding of its roles in microglial function under physiological and neurodegenerative conditions remain rudimentary. Here, we investigate the roles of Cdk5 in microglia using myeloid-specific Cdk5 conditional knockout mice. Using microglia-specific transcriptome profiling, histological analyses, and behavioral assessments, we found that knockout of Cdk5 in microglia for 1 month induced transcriptional changes characterized by upregulation of cell cycle processes and type I interferon signaling genes in both physiological conditions and AD-related amyloidogenesis. In contrast to the robust transcriptional changes, conditional loss of microglial Cdk5 produced minimal effects on the density and morphology of microglia and their phagocytic activity toward myelin debris. Moreover, Cdk5cKO mice exhibited little change in synaptic density and tasks associated with locomotor, anxiety-like, and memory-related behaviors. Our findings indicate that the conditional loss of Cdk5 in microglia induces rapid alterations of microglial transcriptome with minimal or delayed effects on histological and behavioral responses.

neuroscience↗