Richard A. Young’s research while affiliated with Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology and other places

Cells have evolved mechanisms to distribute ~10 billion protein molecules to subcellular compartments where diverse proteins involved in shared functions must assemble. Here, we demonstrate that proteins with shared functions share amino acid sequence codes that guide them to compartment destinations. A protein language model, ProtGPS, was developed that predicts with high performance the compartment localization of human proteins excluded from the training set. ProtGPS successfully guided generation of novel protein sequences that selectively assemble in the nucleolus. ProtGPS identified pathological mutations that change this code and lead to altered subcellular localization of proteins. Our results indicate that protein sequences contain not only a folding code, but also a previously unrecognized code governing their distribution to diverse subcellular compartments.

Introduction Adolescents actively explore future imaginings as they prepare for major educational, work, and personal transitions. Although family members may support exploration of imagined futures, adults outside adolescents' kin network provide access to resources not supplied within the family. The purpose of this study was to understand how adolescents actively draw on social resources of nonfamilial adults relative to their imagined futures. Methods Adolescents attending two schools in British Columbia, Canada participated in a year‐long study involving at least three face to face sessions and biweekly telephone calls. Participants (N = 13; eight identified as boys, four as girls, one as nonbinary; mean age = 14.92, SD = 1.60) were asked to invite nonfamilial adults from their social network to conversations about the future. Results Two youth invited an adult to the research while the majority of participants (n = 11) explicitly changed the protocol by engaging with the researchers rather than bringing nonfamilial adults to the research. The change in the protocol was incorporated into analysis to try to understand participants' engagement in the research. Analysis revealed participants' overall intentions were to engage with adults, using the connections to test and refine imagined futures. Imagined future projects aligned with three clusters: practicing claims, navigating the line in the sand (difficulties crossing into adult realms), and resisting incongruent views of themselves. Conclusion Findings illustrate adolescents' intention to alter the study protocol rather than dropping out and how adolescents' engagement with nonfamilial adults supported opportunities to test and refine imagined futures in the service of constructing identities.

Background Alzheimer’s disease (AD) and other neurodegenerative diseases (NDs) cause substantial health‐related and economic burdens, but progress towards preventative or ameliorative treatments has been limited. Genome‐wide association studies have identified hundreds of risk loci containing single nucleotide polymorphisms (SNPs) that alter risk for these diseases, but >90% of these SNPs are in noncoding regions, which are cell type‐specific and difficult to study. To address this gap, we have characterized the epigenomes of iPSC‐derived neuronal and glial cells and performed CRISPRi single cell screening to dissect the molecular and cellular mechanisms underlying 10 ND risk loci. Method We generated neural progenitors, excitatory neurons, astrocytes and microglia from male and female iPSCs and performed RNA‐seq, H3K27ac ChIP‐seq, and Promoter Capture Hi‐C. We compared these data to those from primary uncultured (ex vivo) human neurons, astrocytes and microglia to compare their enhancer landscapes and ND risk SNP enrichment patterns. To perform CRISPRi single cell screening we integrated a dCas9‐KRAB transgene into an iPSC safe harbor locus and developed a novel lentiviral method that allows for efficient and well‐tolerated delivery of sgRNAs to iPSC‐derived microglia‐like cells (iMGLs). Result iMGLs displayed the strongest correlation of their enhancer landscapes with those of their ex vivo counterparts, as well as highly consistent enrichment of AD and multiple sclerosis (MS) risk SNPs in microglia‐specific enhancers. Enhancer/promoter interactions in iMGLs also overlapped significantly with those from ex vivo microglia. As these results suggest that iMGLs are a suitable model for studying ND risk loci, we performed a CRISPRi single cell screen to identify the target genes and pathways affected at 10 AD and MS risk loci. Conclusion While the enhancer landscapes of iPSC‐derived neuronal and glial cells vary in similarity to their ex vivo counterparts, they display similar ND risk SNP enrichments in cell type‐specific enhancers, suggesting that disease risk SNP mechanisms are largely recapitulated in iPSC‐derived cells. The iMGL epigenome is notably similar to ex vivo microglia, and CRISPRi screening of AD and MS risk loci in these cells will advance our understanding of these diseases and nominate potential therapeutic targets.

Biomolecular condensates are membraneless compartments that organize biochemical processes in cells. In contrast to well-understood mechanisms describing how condensates form and dissolve, the principles underlying condensate patterning – including their size, number and spacing in the cell – remain largely unknown. We hypothesized that RNA, a key regulator of condensate formation and dissolution, influences condensate patterning. Using nucleolar fibrillar centers (FCs) as a model condensate, we found that inhibiting ribosomal RNA synthesis significantly alters the patterning of FCs. Physical theory and experimental observations support a model whereby active RNA synthesis generates a non-equilibrium state that arrests condensate coarsening and thus contributes to condensate patterning. Altering FC condensate patterning by expression of the FC component TCOF1 impairs ribosomal RNA processing, linking condensate patterning to biological function. These results reveal how non-equilibrium states driven by active chemical processes regulate condensate patterning, which is important for cellular biochemistry and function.

As part of a larger study of supportive interventions for young adult newcomers to Canada, this article describes the relevant joint, goal-directed projects in which participants engaged pertinent to their transition to adulthood and to a new country. Fifteen pairs of young adults participated in the intervention over approximately a six-month period. The intervention was based on the identification and support of each dyad’s relevant transition project. The qualitative action-project method was used to gather and analyze data. Unique transition projects were identified and supported for each dyad. These projects are described under three thematic groupings: (a) relationship, with subthemes, relationship as a source of support and navigating relational conflict; (b) social integration, with the subthemes, mutual support, independent pursuit of goals, and relying relationship stability and familiarity; and (c) career, with subthemes, instrumental support and leveraging existing relationship. The findings illustrate both the coaction of developmental and acculturative processes and the how these dyadic transition projects can be identified and supported.