Stablewski, A. | bioRxiv Science

bioRxiv2021

FACT-mediated maintenance of chromatin integrity during transcription is essential for viability of mammalian stem cells

Preservation of nucleosomes during replication has been extensively studied, while the maintenance of nucleosomes during transcription has gotten less attention. The histone chaperone FACT is involved in transcription elongation, although whether it disassembles or assembles nucleosomes during this process is still unclear. We deleted the FACT subunit in adult mice to clarify the function of FACT in mammals. FACT loss was lethal due to the loss of the earliest progenitors in bone marrow and intestine, while mor differentiated cells were not affected. Using cells isolated from several tissues, we showed that FACT loss was lethal only for stem cells but not cells differentiated in vitro. FACT depletion led to increased chromatin accessibility in a transcription-dependent manner, suggesting that nucleosomes are lost during transcription in the absence of FACT. The most prominent response to the loss of nucleosomes was the activation of interferon signaling and the accumulation of immunocytes in sensitive organs. FACT maintained chromatin integrity during transcription in mammalian adult stem cells, suggesting that chromatin transcription in these cells is different from more differentiated cells.

systems biology↗

bioRxiv2020

SERINC5 potently restricts retrovirus infection in vivo

The Serine Incorporator (SERINC) proteins are multipass transmembrane proteins that affect sphingolipid and phosphatidylserine synthesis. Human SERINC5 and SERINC3 were recently shown to possess antiretroviral activity to a number of retroviruses including human immunodeficiency virus (HIV), murine leukemia virus (MLV) and equine infectious anemia virus (EIAV). In the case of MLV, the glycosylated Gag (glyco-Gag) protein was found to counteract SERINC5-mediated restriction in in vitro experiments and that the viral envelope determines virion sensitivity or resistance to SERINC5. However, nothing is known about the in vivo function of SERINC5. Antiretroviral function of a host factor in vitro is not always associated with antiretroviral function in vivo. Using SERINC5-/- mice we generated, we show that mouse SERINC5 (mSERINC5) restriction of MLV infection in vivo is dependent not only on glyco-Gag, but also on the retroviral envelope. Finally, we also examined the in vivo function of the other SERINC gene with known antiretroviral functions, SERINC3. By using SERINC3-/- mice, we found that the murine homologue, mSERINC3, had no antiretroviral role both in vivo and in vitro. This report provides the first data showing that SERINC5 restricts retrovirus infection in vivo and that restriction of retrovirus infectivity in vivo is dependent on both the presence of glyco-Gag and the viral envelope. IMPORTANCEThis study examines for the first time the in vivo function of the Serine Incorporator (SERINC) proteins during retrovirus infection. SERINC3/5 restrict a number of retroviruses including human immunodeficiency virus 1 (HIV-1) and murine leukemia virus (MLV) by blocking their entry into cells. Nevertheless, HIV-1 and MLV encode factors, Nef and glycosylated Gag respectively, that counteract SERINC3/5 in vitro. We recently developed SERINC3 and SERINC5 knockout mice to examine the in vivo function of these genes. We found that SERINC5 potently restricted retrovirus infection in a glycosylated Gag and envelope dependent manner. On the other hand, SERINC3 had no antiviral function. Our findings have implication in the development of therapeutics that target SERINC5 during retrovirus infection.

microbiology↗