[Report] Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes

Science

Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection. To enforce tissue retention, Trm cells up-regulate CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice. The Hobit-Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes, including natural killer T (NKT) cells and liver-resident NK cells, all of which share a common transcriptional program. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.


Transcriptional control of kidney cancer

Science

Clear cell renal cell carcinoma (ccRCC) is a subtype of kidney cancer characterized by inactivation of the von Hippel-Lindau (VHL) gene in 90% of patients. VHL is the substrate recognition component of an E3 ubiqutin ligase complex that targets prolyl-hydroxylated proteins for proteasomal degradation (1). The canonical targets of VHL are the α subunits of hypoxia-inducible factors (HIFs), which are oxygen-labile transcription factors that become constitutively stabilized early in ccRCC development and consequently direct transcriptional programs that promote angiogenesis and rewiring of intracellular metabolism (2–4). Identifying VHL substrates other than HIFαs that escape degradation and contribute to tumorigenesis could represent a new therapeutic approach for ccRCC. On page 290 of this issue, Zhang et al. (5) demonstrate that the transcription factor zinc fingers and homeoboxes 2 (ZHX2) is a previously unidentified VHL target that promotes ccRCC tumorigenesis through regulation of nuclear factor κB (NF-κB) signaling, potentially identifying targets to treat ccRCC.


[Report] Sequential transcriptional waves direct the differentiation of newborn neurons in the mouse neocortex

Science

During corticogenesis, excitatory neurons are born from progenitors located in the ventricular zone (VZ), from where they migrate to assemble into circuits. How neuronal identity is dynamically specified upon progenitor division is unknown. Here, we study this process using a high-temporal-resolution technology allowing fluorescent tagging of isochronic cohorts of newborn VZ cells. By combining this in vivo approach with single-cell transcriptomics in mice, we identify and functionally characterize neuron-specific primordial transcriptional programs as they dynamically unfold. Our results reveal early transcriptional waves that instruct the sequence and pace of neuronal differentiation events, guiding newborn neurons toward their final fate, and contribute to a road map for the reverse engineering of specific classes of cortical neurons from undifferentiated cells.


Neural Network Computation by In Vitro Transcriptional Circuits

Neural Information Processing Systems

The structural similarity of neural networks and genetic regulatory networks todigital circuits, and hence to each other, was noted from the very beginning of their study [1, 2]. In this work, we propose a simple biochemical system whose architecture mimics that of genetic regulation andwhose components allow for in vitro implementation of arbitrary circuits.We use only two enzymes in addition to DNA and RNA molecules: RNA polymerase (RNAP) and ribonuclease (RNase). We develop a rate equation for in vitro transcriptional networks, and derive acorrespondence with general neural network rate equations [3]. As proof-of-principle demonstrations, an associative memory task and a feedforward network computation are shown by simulation. A difference between the neural network and biochemical models is also highlighted: global coupling of rate equations through enzyme saturation can lead to global feedback regulation, thus allowing a simple network without explicit mutual inhibition to perform the winner-take-all computation. Thus, the full complexity of the cell is not necessary for biochemical computation: a wide range of functional behaviors can be achieved with a small set of biochemical components.


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Science

Early life stress increases risk for depression. Here we establish a "two-hit" stress model in mice wherein stress at a specific postnatal period increases susceptibility to adult social defeat stress and causes long-lasting transcriptional alterations that prime the ventral tegmental area (VTA)--a brain reward region--to be in a depression-like state. We identify a role for the developmental transcription factor orthodenticle homeobox 2 (Otx2) as an upstream mediator of these enduring effects. Transient juvenile--but not adult--knockdown of Otx2 in VTA mimics early life stress by increasing stress susceptibility, whereas its overexpression reverses the effects of early life stress. This work establishes a mechanism by which early life stress encodes lifelong susceptibility to stress via long-lasting transcriptional programming in VTA mediated by Otx2.