Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2 S production.

Chemical compounds have recently been introduced as alternative and non-integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling-mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H2 S) production. This metabolic rewiring decreased oxidative phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk-Cn-NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.

N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis.

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification and plays pivotal roles in regulation of mRNA metabolism, while its functions remain elusive. Here, we profile the dynamic landscapes of m6A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m6A demethylase ALKBH5, and find that ALKBH5 plays significant regulatory roles in pancreatic organogenesis. Mechanistic studies reveal that ALKBH5 deficiency reduces the mRNA stability of key pancreatic transcription factors in an m6A and YTHDF2-dependent manner. We further identify that ALKBH5 cofactor α-ketoglutarate can be applied to enhance differentiation. Collectively, our findings identify ALKBH5 as an essential regulator of pancreatic differentiation and highlight that m6A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications.

Quantifying the contributions of human activities and climate change to vegetation net primary productivity dynamics in China from 2001 to 2016.

Vegetation is an important component of the terrestrial ecosystem, driven by climate change and human activities. Quantifying the relative contributions of climate change and anthropogenic activities to vegetation dynamics are essential to cope with global climate change. In this paper, the relative contributions of anthropogenic activities and climate change to net primary productivity (NPP) in China were analyzed by a two-step methodology based on the residual trend analysis (RESTREND). Firstly, the unaltered natural vegetation only affected by climate change (Vclimate) and the vegetation affected by climate change and human activities (Vclimate+human) were separated by the multi-temporal land use land cover (LULC) data. Secondly, RESTREND was applied to NPP of Vclimate and Vclimate+human, respectively, to calculate contributions of climatic factors and human activities to vegetation growth. Results revealed that NPP exhibited a significant increase with 3.13 g C m-2 yr-1 from 2001 to 2016 in China. Climate change and human activities both made favorable impacts on vegetation growth during the study period. Besides, with the separation of Vclimate and Vclimate+human, contributions of climatic factors to vegetation changes increased from 1.57 to 1.88 g C m-2 yr-1, with the proportion of 60.06%. While contributions of human activities to NPP decreased from 1.56 to 1.25 g C m-2 yr-1, with the proportion of 39.94%. Moreover, the average contributions of precipitation, temperature, solar radiation, and other climatic factors to NPP over the entire country were 0.72, 0.24, 0.61, and 0.31 g C m-2 yr-1. Precipitation played a decisive role in vegetation changes in arid and semi-arid regions, temperature was the dominant factor for alpine vegetation dynamics, and solar radiation was beneficial to vegetation growth in most areas of China.

Small molecules promote CRISPR-Cpf1-mediated genome editing in human pluripotent stem cells.

Human pluripotent stem cells (hPSCs) have potential applications in biological studies and regenerative medicine. However, precise genome editing in hPSCs remains time-consuming and labor-intensive. Here we demonstrate that the recently identified CRISPR-Cpf1 can be used to efficiently generate knockout and knockin hPSC lines. The unique properties of CRISPR-Cpf1, including shorter crRNA length and low off-target activity, are very attractive for many applications. In particular, we develop an unbiased drug-selection-based platform feasible for high-throughput screening in hPSCs and this screening system enables us to identify small molecules VE-822 and AZD-7762 that can promote CRISPR-Cpf1-mediated precise genome editing. Significantly, the combination of CRISPR-Cpf1 and small molecules provides a simple and efficient strategy for precise genome engineering.