Inhibiting U1 telescripting: A means to an end for transcription.

In this issue of Molecular Cell, Cugusi et al. (2022) discover that inhibition of U1 telescripting is a novel mechanism that promotes a switch between gene programs in response to heat stress.

Genome organization: Tag it, move it, place it.

Chromosomes are selectively organized within the nuclei of interphase cells reflecting the current fate of each cell and are reorganized in response to various physiological cues to maintain homeostasis. Although substantial progress is being made to establish the various patterns of genome architecture, less is understood on how chromosome folding/positioning is achieved. Here, we discuss recent insights into the cellular mechanisms dictating chromatin movements including the use of epigenetic modifications and allosterically regulated transcription factors, as well as a nucleoskeleton system comprised of actin, myosin, and actin-binding proteins. Together, these nuclear factors help coordinate the positioning of both general and cell-specific genomic architectural features.

Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and triglial dysfunction.

Patients with amyotrophic lateral sclerosis (ALS) can have abnormal TDP-43 aggregates in the nucleus and cytosol of their surviving neurons and glia. Although accumulating evidence indicates that astroglial dysfunction contributes to motor neuron degeneration in ALS, the normal function of TDP-43 in astrocytes are largely unknown, and the role of astroglial TDP-43 loss to ALS pathobiology remains to be clarified. Herein, we show that TDP-43-deleted astrocytes exhibit a cell-autonomous increase in GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43-deleted astrocytes resemble A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause loss of motor neurons in the spinal cord or denervation at the neuromuscular junction. In contrast, there is a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting triglial dysfunction mediated by TDP-43 loss in astrocytes. Moreover, mice with astroglial TDP-43 deletion develop motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice.