Biology subjects

Neumann, E. N.

Publications and source records attributed to Neumann, E. N..

3 recordsLinked to original sources

bioRxiv2026

The diverse functions of viral microproteins

A large fraction of the uncharacterized proteome consists of microproteins. Viruses, rich in microproteins with potent activities, provide a unique system for exploring their functions and evolution. Here, we systematically annotate viral microproteins through a phenotype-first approach: construction of a >50,000-element small ORF library spanning the microprotein-coding potential of human-infecting viruses, followed by broad screens that enrich candidates for high-resolution profiling by Perturb-seq, mass spectrometry, AI-guided structure prediction, and mechanistic studies. This atlas identified >2,000 active microproteins that modulate host pathways through diverse mechanisms, including molecular mimicry, hijacking of key regulators, and altering subcellular localization. We further show the oncogenic potential of BNLF2b, an uncharacterized Epstein-Barr virus microprotein linked to nasopharyngeal carcinoma. Three principles emerge: viral microproteins are diverse and often multifunctional, show widespread convergence toward shared functions, and serve as reservoirs of evolutionary innovation. These findings elucidate how viral microproteins occupy a large functional landscape, establish them as versatile tools for host manipulation, and provide a framework for functional annotation of uncharacterized proteins, contributing toward predictive systems virology.

systems biology↗

bioRxiv2024

Tracing the stepwise Darwinian evolution of a plant halogenase

Halogenation chemistry is rare in plant metabolism, with the chloroalkaloid acutumine produced by Menispermaceae species being the only well characterized example, involving a specialized dechloroacutumine halogenase (DAH) from the iron(II)- and 2-oxoglutarate-dependent dioxygenase (2ODD) superfamily. While DAH is presumed to have evolved from an ancestral 2ODD enzyme, the broader question of how new enzymes arise through Darwinian processes, such as the birth of DAH in Menispermaceae, remains a fundamental challenge in understanding metabolic evolution. Here, we investigate DAHs evolutionary trajectory using the chromosomal-level genome assembly of Menispermum canadense. By analyzing the genomic context of DAH in M. canadense and syntenic regions in related plants, we show that DAH evolved through tandem duplication of an ancestral flavonol synthase (FLS) gene, followed by a series of neofunctionalization and gene loss events. Through structural modeling, molecular dynamics simulations, and site-directed mutagenesis, we identify residue changes enabling the transition from FLS to DAH. This functional switch required traversing a complex evolutionary landscape where adaptive peaks were separated by deep fitness valleys. Our work illustrates how new enzymatic functions can arise through lineage-specific evolutionary pathways that gradually reshape the active site architecture through permissive mutations, ultimately enabling mechanism-switching mutations that establish novel catalytic activities.

biochemistry↗

bioRxiv2020

Dot1L interaction partner AF10 safeguards cell identity during the acquisition of pluripotency

Histone 3 Lysine 79 methylation (H3K79me) is enriched on gene bodies proportional to gene expression levels, and serves as a strong barrier for reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). DOT1L is the sole histone methyltransferase that deposits all three orders - mono, di, and tri methylation - at H3K79. Here we leverage genetic and chemical approaches to parse the specific functions of the higher orders of H3K79me in maintaining cell identity. DOT1L interacts with AF10 (Mllt10) which recognizes unmodified H3K27 and boosts higher order H3K79 methylation. AF10 deletion evicts higher order H3K79me2/3, and reorganizes H3K79me1 to the transcription start site, to facilitate iPSC formation in the absence of steady state transcriptional changes. Instead, AF10 loss redistributes RNA polymerase II to a uniquely pluripotent pattern at highly expressed, rapidly transcribed housekeeping genes. Taken together, we reveal a mechanism for higher order histone methylation located at the gene body in reinforcing cell identity.

genetics↗