On some genetic consequences of social structure, mating systems, dispersal, and sampling
Bárbara R. Parreira and Lounès Chikhi
Many species live in socially structured populations, forming cohesive units with kin structure. Yet, sociality has been neglected by population geneticists under the assumption that social groups can be seen as small demes subjected to significant genetic drift. Such demes are usually considered to be susceptible to inbreeding, with inbreeding avoidance becoming a major force explaining dispersal strategies. We find (pp. E3318–E3326) that social structure is highly effective in maintaining high genotypic and genetic diversity levels, without invoking sex-biased dispersal or inbreeding avoidance mechanisms. These findings should change the way we perceive social groups.
Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation
Wei-wei Gao, Rong-quan Xiao, Bing-ling Peng, Huan-teng Xu, Hai-feng Shen, Ming-feng Huang, Tao-tao Shi, Jia Yi, Wen-juan Zhang, Xiao-nan Wu, Xiang Gao, Xiang-zhi Lin, Pieter C. Dorrestein, Michael G. Rosenfeld, and Wen Liu
HSP70 proteins are well known as molecular chaperones involved in protein folding and quality control. Whether they also function in gene transcription on chromatin, and if so, how they are regulated, remains elusive. Here (pp. E3327–E3336) we report that HSP70 can also regulate gene transcription through its association with chromatin, distinct from its “classic” function as a molecular chaperone. The function of HSP70 in gene transcription is subject to regulation of an arginine methylation on a highly conserved residue in HSP70, which modulates the recruitment of a key component in the pre-initiation complex, and thus transcription initiation. The present study reveals an additional, previously overlooked function of HSP70 chaperone proteins, and links arginine methylation of nonhistone proteins to gene transcriptional regulation.
Mechanochemical tuning of myosin-I by the N-terminal region
Michael J. Greenberg, Tianming Lin, Henry Shuman, and E. Michael Ostap
Myosin molecular motors generate forces in the cell and act as mechanosensors, adjusting their power outputs in response to mechanical loads. Little is known about the structural elements involved in myosin mechanosensing. Our results (pp. E3337–E3344) identify the N-terminal region (NTR) of the myosin-I protein as having an important role in tuning mechanochemistry. Appending the NTR from a highly tension-sensitive myosin (Myo1b) onto a less tension-sensitive motor (Myo1c) changes the identity of the primary force-sensitive transition of Myo1c, making it sensitive to forces <2 pN. Moreover, we show that the NTR stabilizes the post–power-stroke conformation. These results identify the NTR as an important structural element in myosin force sensing and suggest a mechanism for generating diversity of function among myosin isoforms.
Epidermal TRPM8 channel isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner
Gabriel Bidaux, Anne-sophie Borowiec, Dmitri Gordienko, Benjamin Beck, George G. Shapovalov, Loïc Lemonnier, Matthieu Flourakis, Matthieu Vandenberghe, Christian Slomianny, Etienne Dewailly, Philippe Delcourt, Emilie Desruelles, Abigaël Ritaine, Renata Polakowska, Jean Lesage, Mounia Chami, Roman Skryma, and Natalia Prevarskaya
Epidermis, the outer layer of skin, is a protective barrier and a sensing interface. Although deviation of the ambient temperature is one of the most ubiquitous stimuli affecting the skin, the influence of mild cold on epidermal homeostasis is not well understood. Using a large range of techniques, we identified a novel mild-cold sensor protein in keratinocytes and demonstrate its location in the membrane of the endoplasmic reticulum, a major calcium store of the cell, which forms a Ca2+-permeable ion channel (pp. E3345–E3354). Activation of this channel links the Ca2+ release to mitochondrial Ca2+ uptake and, thereby, modulates synthesis of ATP and superoxide involved in control of epidermal homeostasis. Molecular inactivation of this mild-cold sensor protein in mice impairs normal epidermal homeostasis.
A set of NF-κB–regulated microRNAs induces acquired TRAIL resistance in Lung cancer
Young-Jun Jeon, Justin Middleton, Taewan Kim, Alessandro Laganà, Claudia Piovan, Paola Secchiero, Gerard J. Nuovo, Ri Cui, Pooja Joshi, Giulia Romano, Gianpiero Di Leva, Bum-Kyu Lee, Hui-Lung Sun, Yonghwan Kim, Paolo Fadda, Hansjuerg Alder, Michela Garofalo, and Carlo M. Croce
TRAIL (TNF-related apoptosis-inducing ligand) is a promising antitumor agent effective in a very small subset of lung cancer patients with low toxicity. However, the majority of lung tumors are TRAIL-resistant and very little is known about how tumor cells acquire resistance to TRAIL. Here (pp. E3355–E3364), we show that continuous exposure to subtoxic concentrations of TRAIL induces NF-κB–dependent up-regulation of miR-21, miR-30c, and miR-100, which by silencing caspase-8, caspase-3, TRAF7, and FoxO3a further strengthens the NF-κB signaling, inducing acquired TRAIL resistance. Our findings imply that combinatory therapies of NF-κB inhibitors and TRAIL might be a useful therapy to improve the response of lung cancer to TRAIL.
Self-repairing symmetry in jellyfish through mechanically driven reorganization
Michael J. Abrams, Ty Basinger, William Yuan, Chin-Lin Guo, and Lea Goentoro
Animals are endowed with the capacity to repair injuries. In this study (pp. E3365–E3373), we found that, upon amputation, the moon jellyfish Aurelia aurita rearranges existing body parts and recovers radial symmetry within a few days. This unique strategy of self-repair, which we call symmetrization, requires mechanical forces generated by the muscle-based propulsion machinery. We observed a similar strategy in a number of other jellyfish species. This finding may contribute to understanding the evolutionary pressures governing biological self-repair strategies. Beyond biology, this finding may inspire a mechanically driven, self-organizing machinery that recovers essential geometry without regenerating precise forms.
Nuclear matrix-associated protein SMAR1 regulates alternative splicing via HDAC6-mediated deacetylation of Sam68
Kiran Kumar Nakka, Nidhi Chaudhary, Shruti Joshi, Jyotsna Bhat, Kulwant Singh, Subhrangsu Chatterjee, Renu Malhotra, Abhijit De, Manas Kumar Santra, F. Jeffrey Dilworth, and Samit Chattopadhyay
Multiple studies highlight the role of various proteins in regulation of alternative splicing; however, the regulatory role of distinct posttranslational modifications during alternative splicing that contribute to tumorigenesis is enigmatic. Here (pp. E3374–E3383) we report a previously unidentified noncanonical mechanism of regulation of alternative splicing modulated by deacetylation of RNA-binding protein Sam68 (Src-associated substrate during mitosis of 68 kDa) via Scaffold/matrix-associated region-binding protein 1 (SMAR1)–histone deacetylase 6 (HDAC6) complex. SMAR1 in complex with HDAC6 maintains Sam68 in a deacetylated state. We observed that ERK-1/2–dependent phosphorylation of SMAR1, knockdown of SMAR1, or loss of heterozygosity facilitates CD44 variant exon inclusion via Sam68 acetylation and thus confers invasive and metastatic potential in breast tumor cells. Our findings provide key insights into regulation of alternative splicing and the potential for therapeutic intervention during tumor metastasis.
Next-generation libraries for robust RNA interference-based genome-wide screens
Martin Kampmann, Max A. Horlbeck, Yuwen Chen, Jordan C. Tsai, Michael C. Bassik, Luke A. Gilbert, Jacqueline E. Villalta, S. Chul Kwon, Hyeshik Chang, V. Narry Kim, and Jonathan S. Weissman
Genetic screening is a classic approach to identify genes acting in a biological process of interest. In mammalian cells, screens are commonly based on RNA interference (RNAi), in which a short interfering RNA (siRNA) or short-hairpin RNA (shRNA) triggers degradation of cellular messenger RNAs. RNAi approaches are prone to false-positive results because of siRNA/shRNA off-target effects and false-negative results because of siRNAs/shRNAs lacking activity. We previously established that these problems can be minimized with ultracomplex shRNA libraries. Here, we present next-generation shRNA libraries targeting the human and mouse genomes, for which we improved several features to increase shRNA activity (pp. E3384–E3391). In a pilot screen, the new library yields complementary results to clustered regularly interspaced short palindromic repeats interference (CRISPRi), an orthogonal approach we developed recently.
TOE1 is an inhibitor of HIV-1 replication with cell-penetrating capability
Sabina Sperandio, Corinne Barat, Miguel A. Cabrita, Ana Gargaun, Maxim V. Berezovski, Michel J. Tremblay, and Ian de Belle
Understanding the host response to HIV-1 infection may provide important clues to design new strategies to prevent further infection and viral spread. In this report (pp. E3392–E3401), we show that the cellular protein Target Of Egr1 (TOE1) can specifically bind to a HIV-1 regulatory sequence, called the transactivator response element, and inhibit its activity. This inhibition is shown to be sufficient to impair viral transcription and replication in HIV-1–infected T cells. We show that TOE1 is secreted from activated primary T cells, mimicking antigen presentation. Secreted forms of TOE1 cross the plasma membrane of neighboring cells and retain HIV-1 inhibitory activity. These results provide new information on a cellular mediator of HIV-1 inhibition and may guide further therapeutic anti–HIV-1 approaches.
Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis
T. S. Karin Eisinger-Mathason, Vera Mucaj, Kevin M. Biju, Michael S. Nakazawa, Mercy Gohil, Timothy P. Cash, Sam S. Yoon, Nicolas Skuli, Kyung Min Park, Sharon Gerecht, and M. Celeste Simon
Soft-tissue sarcomas are aggressive, often lethal tumors, which are understudied. Few therapies beyond standard resection and traditional chemotherapy/radiation are available. Sarcomas are diverse malignancies, including ∼65 distinct histological subtypes. The existence of common mechanisms underlying multiple subtypes has not previously been shown. We demonstrate that the Hippo pathway, an important regulator of cell proliferation, is deregulated in ≥25% of sarcomas, encompassing multiple commonly diagnosed subtypes (pp. E3402–E3411). When control of the Hippo pathway is lost, expression of the effector protein Yes-Associated Protein (YAP) is stabilized, resulting in higher levels of proliferation. For the first time, to our knowledge, we show that YAP interacts with the forkhead box transcription factor FOXM1 to coregulate critical components of sarcomagenesis, specifically in fibrosarcoma, undifferentiated pleomorphic sarcomas, and liposarcomas.
Hemocyte differentiation mediates the mosquito late-phase immune response against Plasmodium in Anopheles gambiae
Ryan C. Smith, Carolina Barillas-Mury, and Marcelo Jacobs-Lorena
The innate immune response is a major determinant of malaria parasite success in its mosquito host. Previous experiments have implicated LPS-induced TNFα transcription factor (LITAF)-like 3 (LL3) as an integral component of the mosquito immune response to the malaria parasite. This study (pp. E3412–E3420) reports that LL3 influences oocyst survival and demonstrates its role in mosquito blood cell (hemocyte) differentiation in response to parasite infection. Integrating previous data, we provide evidence that hemocytes are critical modulators of the mosquito late-phase immune response. Our findings provide new insight into how parasites are killed in the mosquito host and define major roles for LL3 and the STAT pathways in Plasmodium oocyst survival.
Streptococcus pneumoniae secretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells
Prashant Rai, Marcus Parrish, Ian Jun Jie Tay, Na Li, Shelley Ackerman, Fang He, Jimmy Kwang, Vincent T. Chow, and Bevin P. Engelward
Streptococcus pneumoniae is the most common cause of pneumonia, a leading cause of death globally. Limitations in antibiotic efficacy and vaccines call attention to the need to develop our understanding of host–pathogen interactions to improve mitigation strategies. Here (pp. E3421–E3430), we show that lung cells exposed to S. pneumoniae are subject to DNA damage caused by hydrogen peroxide, which is secreted by strains of S. pneumoniae that carry the spxB gene. The observation that S. pneumoniae secretes hydrogen peroxide at genotoxic and cytotoxic levels is consistent with a model wherein host DNA damage and repair modulate pneumococcal pathogenicity.
Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration
Tetsuji Sekiya, Matthew C. Holley, Kento Hashido, Kazuya Ono, Koichiro Shimomura, Rie T. Horie, Kiyomi Hamaguchi, Atsuhiro Yoshida, Tatsunori Sakamoto, and Juichi Ito
Cell transplantation can restore function in neurodegenerative disorders, but the low rate of functional integration of donor cells into host is a major limiting factor for clinical application. This problem is closely related to the long-standing view that donor cells must be transplanted intraneurally. We show (pp. E3431–E3440) that glial scar, which is common in neurodegenerative conditions, inhibits the survival of intraneurally transplanted cells in our rat glial scar model in the auditory system. However, cells placed on the surface of scar tissue autonomously enter the nerve and become functionally integrated into the host. The glial scar, normally considered to be a barrier to cell transplantation, includes important structural and chemical cues that are disrupted by intraneural delivery but preserved by surface transplantation.
Posterior predictive checks to quantify lack-of-fit in admixture models of latent population structure
David Mimno, David M. Blei, and Barbara E. Engelhardt
Bayesian models, including admixture models, are a powerful framework for articulating complex assumptions about large-scale genetic data; such models are widely used to explore data or to study population-level statistics of interest. However, we assume that a Bayesian model does not oversimplify the complexities in the data, to the point of invalidating our analyses. Here, we develop and study procedures for quantitatively evaluating admixture models of genetic data. Using four large genetic studies, we demonstrate that model checking should be an important part of the modern genetic data analysis pipeline. Our methods (pp. E3441–E3450) help to support inferences drawn from recovered population structure, to protect scientists from being misled by a misspecified model class, and to point scientists toward useful model extensions.